Login| Sign Up| Help| Contact|

Patent Searching and Data


Title:
IDENTIFICATION OF BACTERIA FOR CANCER THERAPY
Document Type and Number:
WIPO Patent Application WO/2019/075452
Kind Code:
A1
Abstract:
Provided herein are methods of identifying bacteria as a likely cancer therapeutic wherein candidate bacteria is cultured with immune cells capable of expressing IP-10 (as well as IL-10 and GM-CSF), pharmaceutical compositions comprising the identified bacteria and methods of treating cancer.

Inventors:
PONICHTERA HOLLY (US)
PAPKOFF JACQUELINE (US)
GOODMAN BRIAN (US)
GARDNER HUMPHREY (US)
SANDY PETER (US)
Application Number:
PCT/US2018/055826
Publication Date:
April 18, 2019
Filing Date:
October 15, 2018
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
EVELO BIOSCIENCES INC (US)
International Classes:
G01N33/50; A61K35/74; A61K38/17; A61K38/19; A61K38/20; C12N5/078; C12Q1/6886; G01N33/574; G01N33/68
Domestic Patent References:
WO2015170158A12015-11-12
WO2016203218A12016-12-22
WO2014181121A12014-11-13
WO2001056387A12001-08-09
Foreign References:
EP2905027A12015-08-12
US6051417A2000-04-18
ES2164011A12002-02-01
Other References:
J. P. ZACKULAR ET AL: "The Gut Microbiome Modulates Colon Tumorigenesis", MBIO, vol. 4, no. 6, 5 November 2013 (2013-11-05), pages e00692 - 13, XP055152082, DOI: 10.1128/mBio.00692-13
CLAESSON M J; WANG Q; O'SULLIVAN O; GREENE-DINIZ R; COLE J R; ROS R P; O'TOOLE P W: "Comparison of two next-generation sequencing technologies for resolving highly complex microbiota composition using tandem variable 16S rRNA gene regions", NUCLEIC ACIDS RES, vol. 38, 2010, pages e200, XP055250083, DOI: doi:10.1093/nar/gkq873
KOMTANTINIDIS K T; RAMETTE A; TIEDJE J M: "The bacterial species definition in the genomic era", PHILOS TRANS R SOC LOND B BIOL SCI, vol. 361, 2006, pages 1929 - 1940
ACHTMAN M; WAGNER M: "Microbial diversity and the genetic nature of microbial species", NAT, REVO MICROBIOL., vol. 6, 2008, pages 431 - 440
KONSTANTINIDIS K T; RAMETTE A; TIEDJE J M: "The bacterial species definition in the genomic era", PHILOS TRANS R SOC LAND B BIOL SCI, vol. 361, 2006, pages 1929 - 1940
PEARSON ET AL., PROC. NATL. ACAD. SCI. USA, vol. 85, 1988, pages 2444
DEVEREUX, J. ET AL., NUCLEIC ACIDS RESEARCH, vol. 12, no. I, 1984, pages 387
ATSCHUL, S. F. ET AL., J MOLEC BIOL, vol. 215, 1990, pages 403
"Guide to Huge Computers, Mrtin J. Bishop", 1994, ACADEMIC PRESS
CARILLO ET AL., SIAM J APPLIED MATH, vol. 48, 1988, pages 1073
SCHOCH ET AL.: "Nuclear ribosomal internal transcribed spacer (ITS) region as a universal DNA barcode marker for Fungi", PNAS, vol. 109, 2012, pages 6241 - 6246, XP055194048, DOI: doi:10.1073/pnas.1117018109
CLAESSON MJ; WANG Q; O'SULLIVAN O; GREENE-DINIZ R; COLE JR; ROSS RP; O'TOOLE PW: "Comparison of two next-generation sequencing technologies for resolving highly complex microbiota composition using tandem variable 16S rRNA gene regions", NUCLEIC ACIDS RES, vol. 3 8, 2010, pages e200
KONSTANTINIDIS KT; RAMETTE A; TIEDJE JM: "The bacterial species definition in the genomic era", PHILOS TRANS R SOC LOND B BIOL SCI, vol. 361, 2006, pages 1929 - 1940
ACHTMAN M; WAGNER M: "Microbial diversity and the genetic nature of microbial species", NAT. REV. MICROBIOL., vol. 6, 2008, pages 431 - 440
LEEKHA ET AL.: "General Principles of Antimicrobial Therapy", MAYO CLIN PROC., vol. 86, no. 2, 2011, pages 156 - 167, XP055372896, DOI: doi:10.4065/mcp.2010.0639
Attorney, Agent or Firm:
JONES, Brendan T. et al. (US)
Download PDF:
Claims:
What is claimed is:

1. A method of identifying bacteria as a likely cancer therapeutic comprising the steps of:

(a) culturing the bacteria with immune cells capable of expressing IP- 10; and

(b) determining the level of IP- 10 expression by the immune cells;

wherein if the level of IP- 10 expression by the immune cells is at least 2-fold higher than the level of IP- 10 expression by the same type of immune cells cultured in the absence of the bacteria, the bacteria are identified as a likely cancer therapeutic.

2. The method of claim 1, wherein the bacteria are identified as a likely cancer therapeutic if the level of IP- 10 expression by the immune cells is at least 5 -fold more than the level of IP- 10 expression by the same type of immune cells cultured in the absence of the bacteria.

3. The method of claim 1, wherein the bacteria are identified as a likely cancer therapeutic if the level of IP- 10 expression by the immune cells is at least 10-fold more than the level of IP- 10 expression by the same type of immune cells cultured in the absence of the bacteria.

4. A method of identifying bacteria as a likely cancer therapeutic comprising the steps of:

(a) culturing the bacteria with immune cells capable of expressing IP- 10; and

(b) determining the level of IP- 10 expression by the immune cells;

wherein if the level of IP- 10 expression by the immune cells is at least 2-fold higher than the level of IP- 10 expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer, the bacteria are identified as a likely cancer therapeutic.

5. The method of claim 4, wherein the bacteria are identified as a likely cancer therapeutic if the level of IP- 10 expression by the immune cells is at least 5 -fold more than the level of IP- 10 expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer, the bacteria are identified as a likely cancer therapeutic.

6. The method of claim 4, wherein the bacteria are identified as a likely cancer therapeutic if the level of IP- 10 expression by the immune cells is at least 10-fold more than the level of IP- 10 expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer, the bacteria are identified as a likely cancer therapeutic.

7. A method of identifying bacteria as being a likely cancer therapeutic comprising the steps of:

(a) culturing the bacteria with immune cells capable of expressing IP- 10 and IL-10; and

(b) determining the ratio of IP- 10 expression to IL-10 expression by the immune cells; wherein if the ratio of IP- 10 expression to IL-10 expression by the immune cells is at least 2-fold more than the ratio of IP- 10 expression to IL-10 expression by the same type of immune cells cultured in the absence of the bacteria, the bacteria are identified as a likely cancer therapeutic.

8. The method of claim 7, wherein the bacteria are identified as a likely cancer therapeutic if the ratio of IP- 10 expression to IL-10 expression by the immune cells is at least 5-fold more than the ratio of IP- 10 expression to IL-10 expression by the same type of immune cells cultured in the absence of the bacteria.

9. The method of claim 7, wherein the bacteria are identified as a likely cancer therapeutic if the ratio of IP- 10 expression to IL-10 expression by the immune cells is at least 10-fold more than the ratio of IP- 10 expression to IL-10 expression by the same type of immune cells cultured in the absence of the bacteria.

10. A method of identifying bacteria as being a likely cancer therapeutic comprising the steps of:

(a) culturing the bacteria with immune cells capable of expressing IP- 10 and IL-10; and

(b) determining the ratio of IP- 10 expression to IL-10 expression by the immune cells; wherein if the ratio of IP- 10 expression to IL-10 expression by the immune cells is at least 2-fold more than the ratio of IP- 10 expression to IL-10 expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer, the bacteria are identified as a likely cancer therapeutic.

11. The method of claim 10, wherein the bacteria are identified as a likely cancer therapeutic if the ratio of IP- 10 expression to IL-10 expression by the immune cells is at least 5 -fold more than the ratio of IP- 10 expression to IL-10 expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer, the bacteria are identified as a likely cancer therapeutic.

12. The method of claim 10, wherein the bacteria are identified as a likely cancer therapeutic if the ratio of IP- 10 expression to IL-10 expression by the immune cells is at least 10-fold more than the ratio of IP- 10 expression to IL-10 expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer, the bacteria are identified as a likely cancer therapeutic.

13. A method of identifying bacteria as being a likely cancer therapeutic comprising the steps of:

(a) culturing the bacteria with immune cells capable of expressing IP- 10 and GM-CSF; and

(b) determining the ratio of IP- 10 expression to GM-CSF expression by the immune cells;

wherein if the ratio of IP- 10 expression to GM-CSF expression by the immune cells is at least 2- fold more than the ratio of IP- 10 expression to GM-CSF expression by the same type of immune cells cultured in the absence of the bacteria, the bacteria are identified as a likely cancer therapeutic.

14. The method of claim 13, wherein the bacteria are identified as a likely cancer therapeutic if the ratio of IP- 10 expression to GM-CSF expression by the immune cells is at least 5 -fold more than the ratio of IP- 10 expression to GM-CSF expression by the same type of immune cells cultured in the absence of the bacteria.

15. The method of claim 13, wherein the bacteria are identified as a likely cancer therapeutic if the ratio of IP- 10 expression to GM-CSF expression by the immune cells is at least 10-fold more than the ratio of IP- 10 expression to GM-CSF expression by the same type of immune cells cultured in the absence of the bacteria.

16. A method of identifying bacteria as being a likely cancer therapeutic comprising the steps of:

(a) culturing the bacteria with immune cells capable of expressing IP- 10 and GM-CSF; and

(b) determining the ratio of IP- 10 expression to GM-CSF expression by the immune cells;

wherein if the ratio of IP- 10 expression to GM-CSF expression by the immune cells is at least 2- fold more than the ratio of IP- 10 expression to GM-CSF expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer, the bacteria are identified as a likely cancer therapeutic.

17. The method of claim 16, wherein the bacteria are identified as a likely cancer therapeutic if the ratio of IP- 10 expression to GM-CSF expression by the immune cells is at least 5 -fold more than the ratio of IP- 10 expression to GM-CSF expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer, the bacteria are identified as a likely cancer therapeutic.

18. The method of claim 16, wherein the bacteria are identified as a likely cancer therapeutic if the ratio of IP- 10 expression to GM-CSF expression by the immune cells is at least 10-fold more than the ratio of IP- 10 expression to GM-CSF expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer, the bacteria are identified as a likely cancer therapeutic.

19. The method of any one of claims 1 to 6, wherein the expression of IP- 10 protein is determined in step (b).

20. The method of any one of claims 1 to 6, wherein the expression of IP- 10 mRNA is determined in step (b).

21. The method of any one of claims 7 to 12, wherein the expressions of IP- 10 protein and IL-10 protein are determined in step (b).

22. The method of any one of claims 7 to 12, wherein the expressions of IP- 10 mRNA and IL-10 mRNA are determined in step (b).

23. The method of any one of claims 13 to 18, wherein the expressions of IP- 10 protein and GM-CSF protein are determined in step (b).

24. The method of any one of claims 13 to 18, wherein the expressions of IP- 10 mRNA and GM-CSF mRNA are determined in step (b).

25. The method of any one of claims 1 to 24, wherein the immune cells are peripheral blood mononuclear cells (PBMCs).

26. The method of any one of claims 1 to 24, wherein the immune cells are macrophages.

27. The method of any one of claims 1 to 24, wherein the immune cells are dendritic cells.

28. The method of any one of claims 1 to 27, wherein the immune cells are from an immune cell line.

29. The method of any one of claim 1 to 27, wherein the immune cells are primary cells.

30. The method of any one of claims 1 to 29, wherein the immune cells are human cells.

31. The method of any one of claims 1 to 30, wherein the bacteria identified as a likely cancer therapeutic are subjected to a further assay.

32. The method of claim 31 , wherein the further assay is an in vivo non-human animal cancer model assay.

33. The method of claim 32, wherein the non-human animal is a mouse, a rat, a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a guinea pig, a sheep, a llama, a monkey, a gorilla or a chimpanzee.

34. The method of any one of claims 1 to 33, further comprising forming a pharmaceutical composition from the bacteria identified as a likely cancer therapeutic.

35. The method of claim 34, further comprising administering the pharmaceutical composition to a subject.

36. The method of claim 35, wherein the subject has cancer.

37. The method of claim 34 or 35, wherein the subject is a non-human animal.

38. The method of claim 37, wherein the non-human animal is a mouse, a rat, a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a guinea pig, a sheep, a llama, a monkey, a gorilla or a chimpanzee.

39. The method of claim 35 or 36, wherein the subject is a human.

40. A pharmaceutical composition comprising the bacteria identified as a likely cancer therapeutic in the method of any one of claims 1 to 30.

41. A pharmaceutical composition comprising bacteria that induce expression of IP- 10 in immune cells at a level that is at least 2-fold higher than the level of IP- 10 expression by the same type of immune cells cultured in the absence of the bacteria.

42. The pharmaceutical composition of claim 41, wherein the bacteria induce expression of IP- 10 in immune cells at a level that is at least 5 -fold higher than the level of IP- 10 expression by the same type of immune cells cultured in the absence of the bacteria.

43. The pharmaceutical composition of claim 41, wherein the bacteria induce expression of IP- 10 in immune cells at a level that is at least 10-fold higher than the level of IP- 10 expression by the same type of immune cells cultured in the absence of the bacteria.

44. A pharmaceutical composition comprising bacteria that induce expression of IP- 10 in immune cells at a level that is at least 2-fold higher than the level of IP- 10 expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer.

45. The pharmaceutical composition of claim 44, wherein the bacteria induce expression of IP- 10 in immune cells at a level that is at least 5 -fold higher than the level of IP- 10 expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer.

46. The pharmaceutical composition of claim 44, wherein the bacteria induce expression of IP- 10 in immune cells at a level that is at least 10-fold higher than the level of IP- 10 expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer.

47. A pharmaceutical composition comprising bacteria that induce expression of a ratio of IP- 10 to IL-10 in immune cells at a level that is at least 2-fold higher than the level of ratio of IP- 10 to IL-10 expression by the same type of immune cells cultured in the absence of the bacteria.

48. The pharmaceutical composition of claim 46, wherein the bacteria induce expression of a ratio of IP- 10 to IL-10 in immune cells at a level that is at least 5-fold higher than the ratio of IP- 10 to IL-10 expression by the same type of immune cells cultured in the absence of the bacteria.

49. The pharmaceutical composition of claim 41, wherein the bacteria induce expression of a ratio of IP- 10 to IL-10 in immune cells at a level that is at least 10-fold higher than the ratio of IP- 10 to IL-10 expression by the same type of immune cells cultured in the absence of the bacteria.

50. A pharmaceutical composition comprising bacteria that induce expression of a ratio of IP- 10 to IL-10 in immune cells at a level that is at least 2-fold higher than the level of ratio of IP- 10 to IL-10 expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer.

51. The pharmaceutical composition of claim 50, wherein the bacteria induce expression of a ratio of IP- 10 to IL-10 in immune cells at a level that is at least 5-fold higher than the ratio of IP- 10 to IL-10 expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer.

52. The pharmaceutical composition of claim 50, wherein the bacteria induce expression of a ratio of IP- 10 to IL-10 in immune cells at a level that is at least 10-fold higher than the ratio of IP- 10 to IL-10 expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer.

53. A pharmaceutical composition comprising bacteria that induce expression of a ratio of IP- 10 to GM-CSF in immune cells at a level that is at least 2-fold higher than the level of ratio of IP- 10 to GM-CSF expression by the same type of immune cells cultured in the absence of the bacteria.

54. The pharmaceutical composition of claim 53, wherein the bacteria induce expression of a ratio of IP- 10 to GM-CSF in immune cells at a level that is at least 5-fold higher than the ratio of IP- 10 to GM-CSF expression by the same type of immune cells cultured in the absence of the bacteria.

55. The pharmaceutical composition of claim 53, wherein the bacteria induce expression of a ratio of IP- 10 to GM-CSF in immune cells at a level that is at least 10-fold higher than the ratio of IP- 10 to GM-CSF expression by the same type of immune cells cultured in the absence of the bacteria.

56. A pharmaceutical composition comprising bacteria that induce expression of a ratio of IP- 10 to GM-CSF in immune cells at a level that is at least 2-fold higher than the level of ratio of IP- 10 to GM-CSF expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer.

57. The pharmaceutical composition of claim 56, wherein the bacteria induce expression of a ratio of IP- 10 to GM-CSF in immune cells at a level that is at least 5-fold higher than the ratio of IP- 10 to GM-CSF expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer.

58. The pharmaceutical composition of claim 56, wherein the bacteria induce expression of a ratio of IP- 10 to GM-CSF in immune cells at a level that is at least 10-fold higher than the ratio of IP- 10 to GM-CSF expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer.

59. The pharmaceutical composition of any one of claims 41 to 58, wherein the immune cells are PBMCs.

60. The pharmaceutical composition of any one of claims 41 to 58, wherein the immune cells are macrophages.

61. The pharmaceutical composition of any one of claims 41 to 58, wherein the immune cells are dendritic cells.

62. The pharmaceutical composition of any one of claims 41 to 61, wherein the composition comprises live, killed, or attenuated bacteria.

63. The pharmaceutical composition of any one of claims 41-62, wherein the bacteria are of a genus, species and/or strain selected from the genera, species and strains listed in Table 1 , Table 2 and/or Table 3 or a genus, species and/or strain that has at least 93% 16s, CRISPR or genomic sequence identity to a genus, species and/or strain selected from the genera, species and strains listed in Table 1, Table 2 and/or Table 3.

64. The pharmaceutical composition of any one of claims 41 to 63, wherein the

pharmaceutical composition is formulated for oral delivery.

65. The pharmaceutical composition of any one of claim 41 to 64, wherein the composition further comprises an additional therapeutic.

66. The pharmaceutical composition of claim 65, wherein the additional therapeutic is a cancer therapeutic.

67. The pharmaceutical composition of claim 66, wherein the cancer therapeutic comprises a chemotherapy agent.

68. The pharmaceutical composition of claim 67, wherein the chemotherapy agent is selected from the group consisting of thiotepa, cyclosphosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, altretamine, triethylenemelamine,

trietylenephosphoramide, triethiylenethiophosphoramide, trimethylolomelamine, bullatacin, bullatacinone, camptothecin, topotecan, bryostatin, callystatin, CC-1065, cryptophycin 1, cryptophycin 8, dolastatin, duocarmycin, eleutherobin, pancratistatin, sarcodictyin, spongistatin, chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimnustine, calicheamicin, dynemicin, clodronate, esperamicin; neocarzinostatin chromophore, aclacinomysins, actinomycin, authrarnycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, methotrexate, 5-fluorouracil (5-FU), denopterin, methotrexate, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6- azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone,

aminoglutethimide, mitotane, trilostane, frolinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elformithine, elliptinium acetate, epothilone, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllinic acid, 2- ethylhydrazide, procarbazine, PSK polysaccharide complex, razoxane, rhizoxin, sizofuran, spirogermanium, tenuazonic acid, triaziquone; 2,2',2"-trichlorotriethylamine, trichothecene, T-2 toxin, verracurin A, roridin A, anguidine, urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, paclitaxel, doxetaxel, chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, methotrexate, cisplatin, oxaliplatin, carboplatin, vinblastine, platinum, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, irinotecan, RFS 2000, difluoromethylomithine, retinoic acid and capecitabine.

69. The pharmaceutical composition of any one of claims 66 to 68, wherein the cancer therapeutic comprises a cancer immunotherapy agent.

70. The pharmaceutical composition of claim 69, wherein the cancer immunotherapy agent comprises an immune checkpoint inhibitor.

71. The pharmaceutical composition of claim 70, wherein the immune checkpoint inhibitor is an antibody or antigen-binding fragment thereof that specifically binds to an immune checkpoint protein.

72. The pharmaceutical composition of claim 71, wherein the immune checkpoint protein is selected from the group consisting of CTLA4, PD-1, PD-L1, PD-L2, A2AR, B7-H3, B7-H4, BTLA, KIR, LAG3, TIM-3 or VISTA.

73. The pharmaceutical composition of claim 70, wherein the immune checkpoint inhibitor is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, AMP- 224, AMP- 514, STI-A1110, TSR-042, RG-7446, BMS-936559, MEDI-4736, MSB-0020718C, AUR-012 and STI-A1010.

74. The pharmaceutical composition of any one of claims 69 to 73, wherein the cancer immunotherapy agent comprises a cancer-specific antibody or antigen-binding fragment thereof.

75. The pharmaceutical composition of claim 74, wherein the cancer-specific antibody or antigen-binding fragment thereof binds specifically to a cancer-associated antigen.

76. The pharmaceutical composition of claim 75, wherein the cancer-associated antigen is selected from the group consisting of adipophilin, AIM-2, ALDHlAl, alpha-actinin-4, alpha- fetoprotein ("AFP"), ARTCl, B-RAF, BAGE-1, BCLX (L), BCR-ABL fusion protein b3a2, beta-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin Dl, Cyclin-Al, dek-can fusion protein, DKK1, EFTUD2, Elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen ("ETA"), ETV6- AML1 fusion protein, EZH2, FGF5, FLT3-ITD, FN1, G250/MN/CAIX, GAGE-1,2,8, GAGE- 3,4,5,6,7, GAS 7, glypican-3, GnTV, gpl00/Pmell7, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL, HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDOl, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kallikrein 4, KIF20A, KK-LC-1, KKLC1, KM-HN-1, KMHNl also known as CCDC110, LAGE-1, LDLR-fucosyltransferaseAS fusion protein, Lengsin, M-CSF, MAGE-Al, MAGE-A10, MAGE- A 12, MAGE-A2, MAGE- A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm-2, ME1, Melan- A/MART- 1 , Meloe, Midkine, MMP-2, MMP-7, MUCl, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88- A, neo-PAP, NFYC, NY-BR-1, NY-ESO-l/LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml-RARalpha fusion protein, polymorphic epithelial mucin ("PEM'), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB 38/NY-MEL- 1 , RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, secernin 1, SIRT2, SNRPD1, SOX10, Spl7, SPA17, SSX-2, SSX-4, STEAPl, survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Triosephosphate isomerase, TRP-l/gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1 and XAGE- 1 b/ GAGED2a.

77. The pharmaceutical composition of claim 76, wherein the cancer associated antigen is a neo-antigen.

78. The pharmaceutical composition any one of claims 69 to 77, wherein the cancer immunotherapy agent comprises a cancer vaccine.

79. The pharmaceutical composition of claim 78, wherein the cancer vaccine comprises a polypeptide comprising an epitope of a cancer-associated antigen.

80. The pharmaceutical composition of claim 79, wherein the cancer-associated antigen is selected from the group consisting of adipophilin, AIM-2, ALDHlAl, alpha-actinin-4, alpha- fetoprotein ("AFP"), ARTCl, B-RAF, BAGE-1, BCLX (L), BCR-ABL fusion protein b3a2, beta-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin Dl, Cyclin-Al, dek-can fusion protein, DKKl, EFTUD2, Elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen ("ETA"), ETV6- AML1 fusion protein, EZH2, FGF5, FLT3-ITD, FN1, G250/MN/CAIX, GAGE-1,2,8, GAGE- 3,4,5,6,7, GAS7, glypican-3, GnTV, gpl00/Pmell7, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL, HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDOl, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kallikrein 4, KIF20A, KK-LC-1, KKLCl, KM-HN-1, KMHNl also known as CCDC110, LAGE-1, LDLR-fucosyltransferaseAS fusion protein, Lengsin, M-CSF, MAGE-Al, MAGE-A10, MAGE-Al 2, MAGE-A2, MAGE- A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm-2, ME1, Melan- A/MART- 1 , Meloe, Midkine, MMP-2, MMP-7, MUCl, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88- A, neo-PAP, NFYC, NY-BR-1, NY-ESO-l/LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml-RARalpha fusion protein, polymorphic epithelial mucin ("PEM'), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB 38/NY-MEL- 1 , RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, secernin 1, SIRT2, SNRPD1, SOX10, Spl7, SPA17, SSX-2, SSX-4, STEAPl, survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Triosephosphate isomerase, TRP-l/gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1 and XAGE- 1 b/ GAGED2a.

81. The pharmaceutical composition of claim 79, wherein the cancer-associated antigen is a neo-antigen.

82. The pharmaceutical composition of any one of claim 79 to 81 wherein the polypeptide is a fusion protein.

83. The pharmaceutical composition of claim 78, wherein the cancer vaccine comprises a nucleic acid encoding an epitope of a cancer-associated antigen.

84. The pharmaceutical composition of claim 83, wherein the cancer-associated antigen is selected from the group consisting of adipophilin, AIM-2, ALDHlAl, alpha-actinin-4, alpha- fetoprotein ("AFP"), ARTCl, B-RAF, BAGE-1, BCLX (L), BCR-ABL fusion protein b3a2, beta-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin Dl, Cyclin-Al, dek-can fusion protein, DKKl, EFTUD2, Elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen ("ETA"), ETV6- AML1 fusion protein, EZH2, FGF5, FLT3-ITD, FN1, G250/MN/CAIX, GAGE-1,2,8, GAGE- 3,4,5,6,7, GAS7, glypican-3, GnTV, gpl00/Pmell7, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL, HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDOl, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kallikrein 4, KIF20A, KK-LC-1, KKLCl, KM-HN-1, KMHNl also known as CCDC110, LAGE-1, LDLR-fucosyltransferaseAS fusion protein, Lengsin, M-CSF, MAGE-Al, MAGE-A10, MAGE-Al 2, MAGE-A2, MAGE- A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm-2, ME1, Melan- A/MART- 1 , Meloe, Midkine, MMP-2, MMP-7, MUCl, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88- A, neo-PAP, NFYC, NY-BR-1, NY-ESO-l/LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml-RARalpha fusion protein, polymorphic epithelial mucin ("PEM'), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB 38/NY-MEL- 1 , RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, secernin 1, SIRT2, SNRPD1, SOX10, Spl7, SPA17, SSX-2, SSX-4, STEAPl, survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Triosephosphate isomerase, TRP-l/gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1 and XAGE- 1 b/ GAGED2a.

85. The pharmaceutical composition of claim 83, wherein the cancer-associated antigen is a neo-antigen.

86. The pharmaceutical composition of any one of claims 83 to 85, wherein the nucleic acid is DNA.

87. The pharmaceutical composition of any one of claims 83 to 85, wherein the nucleic acid ls RNA.

88. The pharmaceutical composition of claim 87, wherein the RNA is mRNA.

89. The pharmaceutical composition of any one of claims 86 to 88, wherein the nucleic acid is in a vector.

90. The pharmaceutical composition of claim 89, wherein the vector is a bacterial vector.

91. The pharmaceutical composition of claim 90, wherein the bacterial vector is selected from the group consisting of Mycobacterium bovis (BCG), Salmonella Typhimurium ssp., Salmonella Typhi ssp., Clostridium sp. spores, Escherichia coli Nissle 1917, Escherichia coli K- 12/LLO, Listeria monocytogenes, and Shigella flexneri.

92. The pharmaceutical composition of claim 89, wherein the vector is a viral vector.

93. The pharmaceutical composition of claim 92, wherein the viral vector is selected from the group consisting of vaccinia, adenovirus, RNA viruses, and replication-defective avipox, replication-defective fowlpox, replication-defective canarypox, replication-defective MVA and replication-defective adenovirus.

94. The pharmaceutical composition any one of claims 69 to 93, wherein the immunotherapy agent comprises an antigen presenting cell (APC) primed with a cancer-specific antigen.

95. The pharmaceutical composition of claim 94, wherein the APC is a dendritic cell, a macrophage or a B cell.

96. The pharmaceutical composition of claim 94 or claim 95, wherein the cancer-associated antigen is selected from the group consisting of adipophilin, AIM-2, ALDHlAl, alpha-actinin-4, alpha-fetoprotein ("AFP"), ARTC1, B-RAF, BAGE-1, BCLX (L), BCR-ABL fusion protein b3a2, beta-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin Dl, Cyclin-Al, dek-can fusion protein, DKK1, EFTUD2, Elongation factor 2, EN AH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen ("ETA"), ETV6-AML1 fusion protein, EZH2, FGF5, FLT3-ITD, FN1, G250/MN/CAIX, GAGE-1,2,8, GAGE-3,4,5,6,7, GAS7, glypican-3, GnTV, gpl00/Pmell7, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL, HLA-Al 1, HLA-A2, HLA-DOB, hsp70-2, IDOl, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kallikrein 4, KIF20A, KK-LC-1, KKLCl, KM-HN-1, KMHNl also known as CCDC110, LAGE-1, LDLR-fucosyltransferaseAS fusion protein, Lengsin, M-CSF, MAGE-Al, MAGE- A 10, MAGE- A 12, MAGE-A2, MAGE- A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm-2, ME1, Melan- A/MART- 1 , Meloe, Midkine, MMP-2, MMP-7, MUCl, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88-A, neo-PAP, NFYC, NY-BR-1, NY-ESO-l/LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml-RARalpha fusion protein, polymorphic epithelial mucin ("PEM'), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB 38/NY-MEL- 1 , RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, secernin 1, SIRT2, SNRPD1, SOX10, Spl7, SPA17, SSX-2, SSX-4, STEAP1, survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Triosephosphate isomerase, TRP-l/gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1 and XAGE- 1 b/ GAGED2a.

97. The pharmaceutical composition of claim 94 or claim 95, wherein the cancer-associated antigen is a neo-antigen.

98. The pharmaceutical composition any one of claims 69 to 97, wherein the immunotherapy agent comprises a cancer-specific chimeric antigen receptor (CAR).

99. The pharmaceutical composition of claim 98, wherein the CAR is administered on the surface of a T cell.

100. The pharmaceutical composition of claim 98 or 99, wherein the CAR binds specifically to a cancer-associated antigen.

101. The pharmaceutical composition of claim 100, wherein the cancer-associated antigen is selected from the group consisting of adipophilin, AIM-2, ALDHIAI, alpha-actinin-4, alpha- fetoprotein ("AFP"), ARTCl, B-RAF, BAGE-1, BCLX (L), BCR-ABL fusion protein b3a2, beta-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin Dl, Cyclin-Al, dek-can fusion protein, DKK1, EFTUD2, Elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen ("ETA"), ETV6- AML1 fusion protein, EZH2, FGF5, FLT3-ITD, FN1, G250/MN/CAIX, GAGE-1,2,8, GAGE- 3,4,5,6,7, GAS7, glypican-3, GnTV, gpl00/Pmell7, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL, HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDOl, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kallikrein 4, KIF20A, KK-LC-1, KKLC1, KM-HN-1, KMHN1 also known as CCDC110, LAGE-1, LDLR-fucosyltransferaseAS fusion protein, Lengsin, M-CSF, MAGE-Al, MAGE-A10, MAGE-Al 2, MAGE-A2, MAGE- A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm-2, ME1, Melan- A/MART- 1 , Meloe, Midkine, MMP-2, MMP-7, MUC1, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88- A, neo-PAP, NFYC, NY-BR-1, NY-ESO-l/LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml-RARalpha fusion protein, polymorphic epithelial mucin ("PEM'), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB 38/NY-MEL- 1 , RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, secernin 1, SIRT2, SNRPD1, SOX10, Spl7, SPA17, SSX-2, SSX-4, STEAPl, survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Triosephosphate isomerase, TRP-l/gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1 and XAGE- 1 b/ GAGED2a.

102. The pharmaceutical composition of claim 99, wherein the cancer associated antigen is a neo-antigen.

103. The pharmaceutical composition any one of claims 69 to 102, wherein the

immunotherapy agent comprises a cancer-specific T cell.

104. The pharmaceutical composition of claim 103, wherein the T cell is a CD4+ T cell.

105. The pharmaceutical composition of claim 104, wherein the CD4+ T cell is a THI T cell, a TH2 T cell or a THI 7 T cell.

106. The pharmaceutical composition of any one of claims 103 to 105, wherein the T cell expresses a T cell receptor specific for a cancer-associated antigen.

107. The pharmaceutical composition of claim 106, wherein the cancer-associated antigen is selected from the group consisting of adipophilin, AIM-2, ALDHlAl, alpha-actinin-4, alpha- fetoprotein ("AFP"), ARTC1, B-RAF, BAGE-1, BCLX (L), BCR-ABL fusion protein b3a2, beta-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin Dl, Cyclin-Al, dek-can fusion protein, DKK1, EFTUD2, Elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen ("ETA"), ETV6- AML1 fusion protein, EZH2, FGF5, FLT3-ITD, FN1, G250/MN/CAIX, GAGE-1,2,8, GAGE- 3,4,5,6,7, GAS7, glypican-3, GnTV, gpl00/Pmell7, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL, HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDOl, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kallikrein 4, KIF20A, KK-LC-1, KKLC1, KM-HN-1, KMHN1 also known as CCDC110, LAGE-1, LDLR-fucosyltransferaseAS fusion protein, Lengsin, M-CSF, MAGE-Al, MAGE-A10, MAGE-Al 2, MAGE-A2, MAGE- A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm-2, ME1, Melan- A/MART- 1 , Meloe, Midkine, MMP-2, MMP-7, MUC1, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88- A, neo-PAP, NFYC, NY-BR-1, NY-ESO-l/LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml-RARalpha fusion protein, polymorphic epithelial mucin ("PEM'), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB 38/NY-MEL- 1 , RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, secernin 1, SIRT2, SNRPD1, SOX10, Spl7, SPA17, SSX-2, SSX-4, STEAP1, survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Triosephosphate isomerase, TRP-l/gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1 and XAGE- 1 b/ GAGED2a.

108. The pharmaceutical composition of any one of claims 69 to 107, wherein the

immunotherapy agent comprises an immune activating protein.

109. The pharmaceutical composition of claim 108, wherein the immune activating protein is a cytokine or chemokine.

110. The pharmaceutical composition of claim 109, wherein the immune activating protein is selected from the group consisting of B lymphocyte chemoattractant ("BLC"), C-C motif chemokine 11 ("Eotaxin-1"), Eosinophil chemotactic protein 2 ("Eotaxin-2"), Granulocyte colony-stimulating factor ("G-CSF"), Granulocyte macrophage colony-stimulating factor ("GM- CSF"), 1-309, Intercellular Adhesion Molecule 1 ("ICAM-l"), Interferon alpha ("IFN-alpha"), Interferon beta ("IFN-beta"), Interferon gamma ("IFN-gamma"), Interlukin-1 alpha ("IL-1 alpha"), Interlukin-1 beta ("IL-1 beta"), Interleukin 1 receptor antagonist ("IL-1 ra"), Interleukin- 2 ("IL-2"), Interleukin-4 ("IL-4"), Interleukin-5 ("IL-5"), Interleukin-6 ("IL-6"), Interleukin-6 soluble receptor ("IL-6 sR"), Interleukin-7 ("IL-7"), Interleukin-8 ("IL-8"), Interleukin- 10 ("IL- 10"), Interleukin- 11 ("IL-l l "), Subumt beta of Interleukin- 12 ("IL-12 p40" or "IL-12 p70"), Interleukin- 13 ("IL-13"), Interleukin- 15 ("IL-15"), Interleukin- 16 ("IL-16"), Interleukin- 17A-F ("IL-17A-F"), Interleukin- 18 ("IL-18"), Interleukin-21 ("IL-21"), Interleukin-22 ("IL-22"), Interleukin-23 ("IL-23"), Interleukin-33 ("IL-33"), Chemokine (C-C motif) Lignad 2 ("MCP-1 "), Macrophage colony-stimulating factor ("M-CSF"), Monokine induced by gamma interferon ("MIG"), Chemokine (C-C motif) ligand 2 ("MIP-1 alpha"), Chemokine (C-C motif) hgand 4 ("MIP-1 beta"), Macrophage inflammatory protein- 1 -delta ("MIP-1 delta"), Platelet-derived growth factor subunit B ("PDGF-BB"), Chemokine (C-C motif) ligand 5, Regulated on

Activation, Normal T cell Expressed and Secreted ("RANTES"), ΉΜΡ metallopeptidase inhibitor 1 ("TIMP-1"), TIMP metallopeptidase inhibitor 2 ("TIMP-2"), Tumor necrosis factor, lymphotoxin-alpha ("TNF alpha"), Tumor necrosis factor, lymphotoxin-beta ("TNF beta"), Soluble TNF receptor type 1 ("sTNFRI"), sTNFRIIAR, Brain-derived neurotrophic factor ("BDNF"), Basic fibroblast growth factor ("bFGF"), Bone morphogenetic protein 4 ("BMP-4"), Bone morphogenetic protein 5 ("BMP-5"), Bone morphogenetic protein 7 ("BMP-7"), Nerve growth factor ("b-NGF"), Epidermal growth factor ("EGF"), Epidermal growth factor receptor ("EGFR"), Endocrine-gland-derived vascular endothelial growth factor ("EG-VEGF"),

Fibroblast growth factor 4 ("FGF-4"), Keratinocyte growth factor ("FGF-7"), Growth differentiation factor 15 ("GDF-15"), Glial cell-derived neurotrophic factor ("GDNF"), Growth Hormone, Heparin-binding EGF-like growth factor ("HB-EGF"), Hepatocyte growth factor ("HGF"), Insulin-like growth factor binding protein 1 ("IGFBP-1 "), Insulin-like growth factor binding protein 2 ("IGFBP-2"), Insulin-like growth factor binding protein 3 (" IGFBP-3"), Insulin-like growth factor binding protein 4 ("IGFBP-4"), Insulin-like growth factor binding protein 6 ("IGFBP-6"), Insulin-like growth factor 1 ("IGF-1"), Insulin, Macrophage colony- stimulating factor ("M-CSF R"), Nerve growth factor receptor ("NGF R"), Neurotrophin-3 ("NTS'1), Neurotrophin-4 ("NT-4"), Osteoclastogenesis inhibitory factor ("Osteoprotegerin"), Platelet- derived growth factor receptors ("PDGF-AA"), Phosphatidylinositol-glycan biosynthesis ("PIGF"), Skp, Cullin, F-box containing complex ("SCF"), Stem cell factor receptor ("SCF R"), Transforming growth factor alpha ("TGFalpha"), Transforming growth factor beta-1 ("TGF beta 1"), Transforming growth factor beta-3 ("TGF beta 3"), Vascular endothelial growth factor ("VEGF"), Vascular endothelial growth factor receptor 2 ("VEGFR2"), Vascular endothelial growth factor receptor 3 ("VEGFR3"), VEGF-D 6Ckine, Tyrosine-protein kinase receptor UFO ("Axl"), Betacellulin ("BTC"), Mucosae-associated epithelial chemokine ("CCL28"), Chemokine (C-C motif) hgand 27 ("CTACK"), Chemokine (C-X-C motif) ligand 16 ("CXCL16"), C-X-C motif chemokine 5 ("ENA-78"), Chemokine (C-C motif) ligand 26 ("Eotaxin-3"), Granulocyte chemotactic protein 2 ("GCP-2"), GRO, Chemokine (C-C motif) ligand 14 ("HCC-l"),

Chemokine (C-C motif) ligand 16 ("HCC-4"), Interleukin-9 ("IL-9"), Interleukin-17 F ("IL- 17F"), Interleukin- 18-binding protein ("IL-18 BPa"), Interleukin-28 A ("IL-28A"), Interleukin 29 ("IL-29"), Interleukin 31 ("IL-31"), C-X-C motif chemokine 10 ("IP-10"), Chemokine receptor CXCR3 ("I-TAC"), Leukemia inhibitory factor ("LIF"), Light, Chemokine (C motif) ligand ("Lymphotactin"), Monocyte chemoattractant protein 2 ("MCP-2"), Monocyte chemoattractant protein 3 ("MCP-3"), Monocyte chemoattractant protein 4 ("MCP-4"),

Macrophage-derived chemokine ("MDC"), Macrophage migration inhibitory factor ("MIF"), Chemokine (C-C motif) ligand 20 ("MIP-3 alpha"), C-C motif chemokine 19 ("MIP-3 beta"), Chemokine (C-C motif) ligand 23 ("MPIF-1 "), Macrophage stimulating protein alpha chain ("MSPalpha"), Nucleosome assembly protein 1 -like 4 ("NAP-2"), Secreted phosphoprotein 1 ("Osteopontin"), Pulmonary and activation-regulated cytokine ("PARC"), Platelet factor 4 ("PF4"), Stroma cell-derived factor- 1 alpha ("SDF-1 alpha"), Chemokine (C-C motif) ligand 17 ("TARC"), Thymus-expressed chemokine ("TECK"), Thymic stromal lymphopoietin ("TSLP 4- IBB"), CD 166 antigen ("ALCAM"), Cluster of Differentiation 80 ("B7-1 "), Tumor necrosis factor receptor superfamily member 17 ("BCMA"), Cluster of Differentiation 14 ("CD14"), Cluster of Differentiation 30 ("CD30"), Cluster of Differentiation 40 ("CD40 Ligand"),

Carcinoembryonic antigen-related cell adhesion molecule 1 (biliary glycoprotein) ("CEACAM- 1"), Death Receptor 6 ("DR6"), Deoxythymidine kinase ("Dtk"), Type 1 membrane glycoprotein ("Endoglin"), Receptor tyrosine-protein kinase erbB-3 ("ErbB3"), Endothelial-leukocyte adhesion molecule 1 ("E-Selectin"), Apoptosis antigen 1 ("Fas"), Fms-like tyrosine kinase 3 ("Flt-3L"), Tumor necrosis factor receptor superfamily member 1 ("GITR"), Tumor necrosis factor receptor superfamily member 14 ("HVEM"), Intercellular adhesion molecule 3 ("ICAM- 3"), IL-1 R4, IL-1 RI, IL-10 Rbeta, IL-17R, IL-2Rgamma, IL-21R, Lysosome membrane protein 2 ("LIMPII"), Neutrophil gelatinase-associated lipocalin ("Lipocalin-2"), CD62L ("L-Selectin"), Lymphatic endothelium ("LYVE-1"), MHC class I polypeptide-related sequence A ("MICA"), MHC class I polypeptide-related sequence B ("MICB"), NRGl-betal, Beta-type platelet-derived growth factor receptor ("PDGF Rbeta"), Platelet endothelial cell adhesion molecule ("PECAM- 1"), RAGE, Hepatitis A virus cellular receptor 1 ("TIM-1 "), Tumor necrosis factor receptor superfamily member IOC ("TRAIL R3"), Trappin protein transglutaminase binding domain ("Trappin-2"), Urokinase receptor ("uPAR"), Vascular cell adhesion protein 1 ("VCAM-1"), XEDARActivin A, Agouti-related protein ("AgRP"), Ribonuclease 5 ("Angiogenin"),

Angiopoietin 1, Angiostatin, Catheprin S, CD40, Cryptic family protein IB ("Cripto-1 "), DAN, Dickkopf-related protein 1 ("DKK-1 "), E-Cadherin, Epithelial cell adhesion molecule

("EpCAM"), Fas Ligand (FasL or CD95L), Fcg RIIB/C, FoUistatin, Galectin-7, Intercellular adhesion molecule 2 ("ICAM-2"), IL-13 RI, IL-13R2, IL-17B, IL-2 Ra, IL-2 Rb, IL-23, LAP, Neuronal cell adhesion molecule ("NrCAM"), Plasminogen activator inhibitor- 1 ("PAI-1"), Platelet derived growth factor receptors ("PDGF-AB"), Resistin, stromal cell-derived factor 1 ("SDF-1 beta"), sgpl30, Secreted frizzled-related protein 2 ("ShhN"), Sialic acid-binding immunoglobulin-type lectins ("Siglec-5"), ST2, Transforming growth factor-beta 2 ("TGF beta 2"), Tie-2, Thrombopoietin ("TPO"), Tumor necrosis factor receptor superfamily member 10D ("TRAIL R4"), Triggering receptor expressed on myeloid cells 1 ("TREM-1"), Vascular endothelial growth factor C ("VEGF-C"), VEGFRlAdiponectin, Adipsin ("AND"), Alpha- fetoprotein ("AFP"), Angiopoietin-like 4 ("ANGPTL4"), Beta-2-microglobulin ("B2M"), Basal cell adhesion molecule ("BCAM"), Carbohydrate antigen 125 ("CA125"), Cancer Antigen 15-3 ("CA15-3"), Carcinoembryonic antigen ("CEA"), cAMP receptor protein ("CRP"), Human Epidermal Growth Factor Receptor 2 ("ErbB2"), Follistatin, Follicle-stimulating hormone ("FSH"), Chemokine (C-X-C motif) ligand 1 ("GRO alpha"), human chorionic gonadotropin ("beta HCG"), Insulin-like growth factor 1 receptor ("IGF-l sR"), IL-1 sRII, IL-3, IL-18 Rb, IL- 21, Leptin, Matrix metalloproteinase-1 ("MMP-1"), Matrix metalloproteinase-2 ("MMP-2"), Matrix metalloproteinase-3 ("MMP-3"), Matrix metalloproteinase-8 ("MMP-8"), Matrix metalloproteinase-9 ("MMP-9"), Matrix metalloproteinase-10 ("MMP-10"), Matrix

metalloproteinase-13 ("MMP-13"), Neural Cell Adhesion Molecule ("NCAM-1 "), Entactin ("Nidogen-1 "), Neuron specific enolase ("NSE"), Oncostatin M ("OSM"), Procalcitonin, Prolactin, Prostate specific antigen ("PSA"), Sialic acid-binding Ig-like lectin 9 ("Siglec-9"), ADAM 17 endopeptidase ("TACE"), Thyroglobulin, Metalloproteinase inhibitor 4 ("TIMP-4"), TSH2B4, Disintegrin and metalloproteinase domain- containing protein 9 ("ADAM-9"), Angiopoietin 2, Tumor necrosis factor ligand superfamily member 13/ Acidic leucine-rich nuclear phosphoprotein 32 family member B ("APRIL"), Bone morphogenetic protein 2 ("BMP- 2"), Bone morphogenetic protein 9 ("BMP-9"), Complement component 5a ("C5a"), Cathepsin L, CD200, CD97, Chemerin, Tumor necrosis factor receptor superfamily member 6B ("DcR3"), Fatty acid-binding protein 2 ("FABP2"), Fibroblast activation protein, alpha ("FAP"), Fibroblast growth factor 19 ("FGF-19"), Galectin-3, Hepatocyte growth factor receptor ("HGF R"), IFN- gammalpha/beta R2, Insulin-like growth factor 2 ("IGF-2"), Insulin-like growth factor 2 receptor ("IGF-2 R"), Interleukin-1 receptor 6 ("IL-1R6"), Interleukin 24 ("IL-24"), Interleukin 33 ("IL- 33", Kallikrein 14, Asparaginyl endopeptidase ("Legumain"), Oxidized low-density lipoprotein receptor 1 ("LOX-1"), Mannose-binding lectin ("MBL"), Neprilysin ("NEP"), Notch homolog 1, translocation-associated (Drosophila) ("Notch-1"), Nephroblastoma overexpressed ("NOV"), Osteoactivin, Programmed cell death protein 1 ("PD-1"), N-acetylmuramoyl-L-alanine amidase ("PGRP-5"), Serpin A4, Secreted frizzled related protein 3 ("sFRP-3"), Thrombomodulin, Tolllike receptor 2 ("TLR2"), Tumor necrosis factor receptor superfamily member 10A ("TRAIL Rl"), Transferrin ("TRF"), WIF-lACE-2, Albumin, AMICA, Angiopoietin 4, B-cell activating factor ("BAFF"), Carbohydrate antigen 19-9 ("CA19-9"), CD 163 , Clustenn, CRT AM, Chemokine (C-X-C motif) ligand 14 ("CXCL14"), Cystatin C, Decorin ("DCN"), Dickkopf- related protein 3 ("Dkk-3"), Delta-like protein 1 ("DLL1 "), Fetuin A, Heparin-binding growth factor 1 ("aFGF"), Folate receptor alpha ("FOLRl"), Furin, GPCR-associated sorting protein 1 ("GASP-1 "), GPCR-associated sorting protein 2 ("GASP-2"), Granulocyte colony-stimulating factor receptor ("GCSF R"), Serine protease hepsin ("HAI-2"), Interleukin- 17B Receptor ("IL- 17B R"), Interleukin 27 ("IL-27"), Lymphocyte-activation gene 3 ("LAG-3"), Apolipoprotein A- V ("LDL R"), Pepsinogen I, Retinol binding protein 4 ("RBP4"), SOST, Heparan sulfate proteoglycan ("Syndecan-1"), Tumor necrosis factor receptor superfamily member 13B

("TACI"), Tissue factor pathway inhibitor ("TFPI"), TSP-1, Tumor necrosis factor receptor superfamily, member 10b ("TRAIL R2"), TRANCE, Troponin I, Urokinase Plasminogen Activator ("uPA"), Cadherin 5, type 2 or VE-cadherin (vascular endothelial) also known as CD144 ("VE-Cadherin"), WNTl-inducible-signaling pathway protein 1 ("WISP-1"), and Receptor Activator of Nuclear Factor κ B ("RANK").

111. The pharmaceutical composition of any one of claims 69 to 110, wherein the

immunotherapy agent comprises an adjuvant.

112. The pharmaceutical composition of claim 111, wherein the adjuvant is selected from the group consisting of an immune modulatory protein, Adjuvant 65, a-GalCer, aluminum phosphate, aluminum hydroxide, calcium phosphate, β-Glucan Peptide, CpG DNA, GPI-OlOO, lipid A, lipopolysaccharide, Lipovant, Montanide, N-acetyl-muramyl-L-alanyl-D-isoglutamine, Pam3CSK4, quil A and trehalose dimycolate.

113. The pharmaceutical composition of any one of claims 66 to 112, wherein the cancer therapeutic comprises an angiogenesis inhibitor.

114. The pharmaceutical composition of claim 113, wherein the angiogenesis inhibitor is selected from the group consisting of Bevacizumab (Avastin®), Ziv-aflibercept (Zaltrap®), Sorafenib (Nexavar®), Sunitinib (Sutent®), Pazopanib (Votrient®), Regorafenib (Stivarga®), and Cabozantinib (Cometriq™).

115. The pharmaceutical composition of any one of claims 66 to 114, wherein the cancer therapeutic comprises an antibiotic.

116. The pharmaceutical composition of claim 115, wherein the antibiotic is selected from the group consisting of aminoglycosides, ansamycins, carbacephems, carbapenems, cephalosporins, glycopeptides, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans,

oxazolidonones, penicillins, polypeptide antibiotics, quinolones, fluoroquinolone, sulfonamides, tetracyclines, anti-mycobacterial compounds and combinations thereof.

117. The pharmaceutical composition of any one of claims 66 to 116, wherein the cancer therapeutic comprises therapeutic bacteria.

118. The pharmaceutical composition of claim 117, wherein the composition further comprises a prebiotic.

119. The pharmaceutical composition of claim 118, wherein the prebiotic is a

fructooligosaccharide, a galactooligosaccharide, a trans-galactooligosaccharide, a

xylooligosaccharide, a chitooligosaccharide, a soy oligosaccharides, a gentiooligosaccharide, an isomaltooligosaccharide, a mannooligosaccharide, a maltooligosaccharide, a

mannanoligosaccharide, lactulose, lactosucrose, palatinose, glycosyl sucrose, guar gum, gum Arabic, tagalose, amylose, amylopectin, pectin, xylan, or a cyclodextrin.

120. The pharmaceutical composition of any one of claims 60 to 119, wherein the additional therapeutic comprises an antibiotic.

121. The pharmaceutical composition of claim 120, wherein the antibiotic is selected from the group consisting of aminoglycosides, ansamycins, carbacephems, carbapenems, cephalosporins, glycopeptides, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans,

oxazolidonones, penicillins, polypeptide antibiotics, quinolones, fluoroquinolone, sulfonamides, tetracyclines, anti-mycobacterial compounds and combinations thereof.

122. The pharmaceutical composition of any one of claims 120 or 121, wherein the additional therapeutic comprises therapeutic bacteria.

123. The pharmaceutical composition of any one of claims 60 to 122, wherein the additional therapeutic comprises an immunosuppressive agent, a DMARD, a pain-control drug, a steroid, a non-steroidal antiinflammatory drug (NSAID), or a cytokine antagonist, and combinations thereof.

124. The pharmaceutical composition of claim 123, wherein the additional therapeutic is selected from the group consisting of cyclosporin, retinoids, corticosteroids, propionic acid derivative, acetic acid derivative, enolic acid derivatives, fenamic acid derivatives, Cox-2 inhibitors, lumiracoxib, ibuprophen, cholin magnesium salicylate, fenoprofen, salsalate, difunisal, tolmetin, ketoprofen, flurbiprofen, oxaprozin, indomethacin, sulindac, etodolac, ketorolac, nabumetone, naproxen, valdecoxib, etoricoxib, MK0966; rofecoxib, acetominophen, Celecoxib, Diclofenac, tramadol, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, mefanamic acid, meclofenamic acid, flufenamic acid, tolfenamic, valdecoxib, parecoxib, etodolac, indomethacin, aspirin, ibuprophen, firocoxib, methotrexate (MTX), antimalarial drugs (e.g., hydroxychloroquine and chloroquine), sulfasalazine, Leflunomide, azathioprine, cyclosporin, gold salts, minocycline, cyclophosphamide, D-penicillamine, minocycline, auranofin, tacrolimus, myocrisin, chlorambucil, TNF alpha antagonists (e.g., TNF alpha antagonists or TNF alpha receptor antagonists), e.g., ADALIMUMAB (Humira®), ETANERCEPT (Enbrel®), INFLIXIMAB (Remicade®; TA-650), CERTOLIZUMAB PEGOL (Cimzia®; CDP870), GOLIMUMAB (Simpom®; CNTO 148), ANAKINRA (Kineret®), RITUXTMAB (Rituxan®; MabThera®), ABATACEPT (Orencia®), TOCILIZUMAB

(RoActemra /Actemra®), integrin antagonists (TYSABRI® (natalizumab)), IL-1 antagonists (ACZ885 (Ilaris)), Anakinra (Kineret®)), CD4 antagonists, IL-23 antagonists, IL-20 antagonists, IL-6 antagonists, BLyS antagonists (e.g., Atacicept, Benlysta®/ LymphoStat-B® (belimumab)), p38 Inhibitors, CD20 antagonists (Ocrelizumab, Ofatumumab (Arzerra®)), interferon gamma antagonists (Fontolizumab), prednisolone, Prednisone, dexamethasone, Cortisol, cortisone, hydrocortisone, methylprednisolone, betamethasone, triamcinolone, beclometasome,

fludrocortisone, deoxycorticosterone, aldosterone, Doxycycline, vancomycin, pioglitazone, SBI- 087, SCIO-469, Cura-100, Oncoxin + Viusid, TwHF, Methoxsalen, Vitamin D - ergocalciferol, Milnacipran, Paclitaxel, rosig tazone, Tacrolimus (Prograf®), RADOOl, rapamune, rapamycin, fostamatinib, Fentanyl, XOMA 052, Fostamatinib disodium,rosightazone, Curcumin

(Longvida™), Rosuvastatin, Maraviroc, ramipnl, Milnacipran, Cobiprostone, somatropin, tgAAC94 gene therapy vector, MK0359, GW856553, esomeprazole, everolimus, trastuzumab, JAKl and JAK2 inhibitors, pan JAK inhibitors, e.g., tetracyclic pyridone 6 (P6), 325, PF-956980, denosumab, IL-6 antagonists, CD20 antagonistis, CTLA4 antagonists, IL-8 antagonists, IL-21 antagonists, IL-22 antagonist, integrin antagonists (Tysarbri® (natalizumab)), VGEF antagnosits, CXCL antagonists, MMP antagonists, defensin antagonists, IL-1 antagonists (including IL-1 beta antagonsits), and IL-23 antagonists (e.g., receptor decoys, antagonistic antibodies, ).

125. The pharmaceutical composition of claim 124, wherein the immunosuppressive agent is acorticosteroids, mesalazine, mesalamine, sulfasalazine, sulfasalazine derivatives,

immunosuppressive drugs, cyclosporin A, mercaptopurine, azathiopurine, prednisone, methotrexate, antihistamines, glucocorticoids, epinephrine, theophylline, cromolyn sodium, anti- leukotrienes, anti-cholinergic drugs for rhinitis, TLR antagonists, inflammasome inhbitors, anticholinergic decongestants, mast-cell stabilizers, monoclonal anti-IgE antibodies, vaccines (e.g., vaccines used for vaccination where the amount of an allergen is gradually increased), cytokine inhibitors, such as anti-IL-6 antibodies, TNF inhibitors such as infliximab, adalimumab, certolizumab pegol, golimumab, or etanercept, and combinations thereof.

126. A method of treating cancer in a subject comprising administering to the subject a pharmaceutical composition according to any one of claims 40-125.

127. A method of inducing IP- 10 expression in a subject comprising administering to the subject a pharmaceutical composition according to any one of claims 40-125.

128. A method of inducing an elevated ratio of IP- 10 expression to IL-10 expression in a subject comprising administering to the subject a pharmaceutical composition according to any one of claims 40-125.

129. A method of inducing an elevated ratio of IP- 10 expression to GM-CSF expression in a subject comprising administering to the subject a pharmaceutical composition according to any one of claims 40-125.

130. A method of augmenting a microbiome in a subject who has cancer, the method comprising administering to the subject a pharmaceutical composition according to any one of claims 40 to 125 to the subject such that the bacteria are added to a niche in the subject.

131. A method of depleting a tumor of cancer-associated bacteria in a subject, the method comprising administering to the subject a pharmaceutical composition according to any one of claims 40 to 125 to the subject such that the bacteria are added to a niche in the subject.

132. A method of changing a tumor microbiome in a subject, the method comprising administering to the subject a pharmaceutical composition according to any one of claims 40 to 125 to the subject such that the bacteria are added to a niche in the subject.

133. A method of changing a mesenteric lymph node microbiome in a subject, the method comprising administering to the subject a pharmaceutical composition according to any one of claims 40 to 125 to the subject such that the bacteria are added to a niche in the subject.

134. A method of activating epithelial cells in a subject, the method comprising administering to the subject a pharmaceutical composition according to any one of claims 40 to 125 to the subject such that the bacteria are added to a niche in the subject.

135. The method of any one of claims 130 to 134, wherein the niche is in the gastrointestinal tract of the subject.

136. The method of any one of claims 130 to 134, wherein the niche is in the urogenital tract of the subject.

137. The method of any one of claims 130 to 134, wherein the niche is in the respiratory tract of the subject.

138. The method of any one of claims 126 to 134, wherein the bacteria are a cancer associated bacterium.

139. The method of claim 138, wherein the cancer associated bacterium is of a species selected from the group of the bacterial species listed in Table 2.

140. The method of claim 138 or 139, wherein the bacteria are an obligate anaerobic bacterium.

141. The method of claim 140, wherein the obligate anaerobic bacterium is of a genus selected from the group consisting of Bacteroides, Prevotella, Porphyromonas, Fusobacterium, Bilophila, Sutterella, Peptostreptococcus, Clostridium, Actinomyces Propionibacterium, Eubacterium, Lactobacillus, Streptococcus and Veillonella.

142. The method of any one of claims 126 to 141, wherein the cancer is selected from the group consisting of hematological malignancy, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, undifferentiated cell leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocyte leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, plasmacytic leukemia, promyelocytic leukemia, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiennoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniform carcinoma, gelatinous carcinoma, giant cell carcinoma, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, carcinoma villosum, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, naspharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, endometrial sarcoma, stromal sarcoma, Ewing' s sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma,

immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, telangiectatic sarcoma, Hodgkin's Disease, Non-Hodgkin's

Lymphoma, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, small-cell lung tumors, primary brain tumors, stomach cancer, colon cancer, malignant pancreatic insulanoma, malignant carcinoid, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, cervical cancer, endometrial cancer, adrenal cortical cancer, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, nodular melanoma subungal melanoma, superficial spreading melanoma, plasmacytoma, colorectal cancer, rectal cancer, Merkel Cell carcinoma, and salivary gland carcinoma.

143. The method of any one of claims 126 to 142, wherein the pharmaceutical composition is administered orally.

144. The method of any one of claims 126 to 142, wherein the pharmaceutical composition is administered intravenously.

145. The method of any one of claims 126 to 142, wherein the pharmaceutical composition is administered intratumorally.

146. The method of any one of claims 126 to 142, wherein the pharmaceutical composition is administered subtumorally.

147. The method of any one of claims 126 to 142, wherein the pharmaceutical composition is administered by subcutaneous, intradermal, or intraperitoneal injection.

148. The method of any one of claims 126 to 142, wherein the pharmaceutical composition is administered intratumorally with a controlled release matrix.

149. The method of any one of claims 126 to 148, wherein administration of the

pharmaceutical composition treats the cancer.

150. The method of any one of claims 126 to 149, wherein administration of the

pharmaceutical composition induces an anti-tumor immune response.

151. The method of any one of claims 126 to 149, wherein the administration of the pharmaceutical composition induces expression of IP- 10 in the subject.

152. The method of any one of claims 126 to 151, wherein the method further comprises administering to the subject a second cancer therapy.

153. The method of claim 152, wherein the second cancer therapy comprises the

administration of a chemotherapy agent to the subject.

154. The method of claim 153, wherein the chemotherapy agent is selected from the group consisting of thiotepa, cyclosphosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide, trimethylolomelamine, bullatacin, buUatacinone, camptothecin, topotecan, bryostatin, callystatin, CC-1065, cryptophycin 1, cryptophycin 8, dolastatin, duocarmycin, eleutherobin, pancratistatin, sarcodictyin, spongistatin, chlorambucil,

chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine,

mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimnustine, calicheamicin, dynemicin, clodronate, esperamicin; neocarzinostatin chromophore, aclacinomysins, actinomycin, authrarnycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, methotrexate, 5-fluorouracil (5-FU), denopterin, methotrexate, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6- azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone,

aminoglutethimide, mitotane, trilostane, frolinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elformithine, elliptinium acetate, epothilone, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllinic acid, 2- ethylhydrazide, procarbazine, PSK polysaccharide complex, razoxane, rhizoxin, sizofuran, spirogermanium, tenuazonic acid, triaziquone; 2,2',2"-trichlorotriethylamine, trichothecene, T-2 toxin, verracurin A, roridin A, anguidine, urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, paclitaxel, doxetaxel, chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, methotrexate, cisplatin, oxaliplatin, carboplatin, vinblastine, platinum, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, irinotecan, RFS 2000, difluoromethylomithine, retinoic acid and capecitabine.

155. The method of any one of claims 152 to 154, wherein the second cancer therapy comprises cancer immunotherapy.

156. The method of claim 155, wherein the cancer immunotherapy comprises administering an immune checkpoint inhibitor to the subject.

157. The method of claim 156, wherein the immune checkpoint inhibitor is an antibody or antigen-binding fragment thereof that specifically binds to an immune checkpoint protein.

158. The method of claim 157, wherein the immune checkpoint inhibitor is an siRNA molecule, an shRNA molecule or an antisense RNA molecule that inhibits expression of an immune checkpoint protein.

159. The method of claim 157 or 158, wherein the immune checkpoint protein is CTLA4, PD- 1, PD-L1, PD-L2, A2AR, B7-H3, B7-H4, BTLA, KIR, LAG3, TIM-3 or VISTA.

160. The method of claim 156, wherein the immune checkpoint inhibitor is atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, pidilizumab, AMP-224, AMP- 514, BGB-A317, STI-Al l lO, TSR-042, RG-7446, BMS-936559, MEDI-4736, MSB-0020718C, AUR-012 or STI-A1010.

161. The method of any one of claims 155 to 160, wherein the cancer immunotherapy comprises administration of a cancer-specific antibody or antigen-binding fragment thereof to the subject.

162. The method of claim 161, wherein the cancer-specific antibody or antigen-binding fragment thereof binds specifically to a cancer-associated antigen.

163. The method of claim 162, wherein the cancer-associated antigen is selected from the group consisting of adipophilin, AIM-2, ALDH1A1, alpha-actinin-4, alpha-fetoprotein ("AFP"), ARTCl, B-RAF, BAGE-1, BCLX (L), BCR-ABL fusion protein b3a2, beta-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin Dl, Cyclin-Al, dek-can fusion protein, DKK1, EFTUD2, Elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen ("ETA"), ETV6-AML1 fusion protein, EZH2, FGF5, FLT3-ITD, FNl, G250/MN/CAIX, GAGE-1,2,8, GAGE-3,4,5,6,7, GAS7, glypican-3, GnTV, gpl00/Pmell7, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL, HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDOl, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kalhkrein 4, KIF20A, KK-LC-1, KKLC1, KM-HN-1, KMHN1 also known as CCDCl lO, LAGE-1, LDLR-fucosyltransferaseAS fusion protein, Lengsin, M-CSF, MAGE-Al, MAGE-Al 0, MAGE-Al 2, MAGE-A2, MAGE- A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MCIR, MCSP, mdm-2, MEl, Melan- A/MART- 1 , Meloe, Midkine, MMP-2, MMP-7, MUCl, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88-A, neo-PAP, NFYC, NY- BR-1, NY-ESO-l/LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml- RARalpha fusion protein, polymorphic epithelial mucin ("PEM"), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB38/NY-MEL- 1 , RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, secernin 1, SIRT2, SNRPDl, SOX10, Spl7, SPA17, SSX-2, SSX-4, STEAPl, survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Tnosephosphate isomerase, TRP-l/gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1 and XAGE- 1 b/ GAGED2a.

164. The method of claim 162, wherein the cancer associated antigen is a neo-antigen.

165. The method any one of claims 66 to 164, wherein the cancer immunotherapy comprises administration of a cancer vaccine to the subject.

166. The method of claim 165, wherein the cancer vaccine comprises a polypeptide comprising an epitope of a cancer-associated antigen.

167. The method of claim 166, wherein the cancer-associated antigen is selected from the group consisting of adipophilin, AIM-2, ALDH1A1, alpha-actinin-4, alpha-fetoprotein ("AFP"), ARTCl, B-RAF, BAGE-1, BCLX (L), BCR-ABL fusion protein b3a2, beta-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin Dl, Cyclin-Al, dek-can fusion protein, DKK1, EFTUD2, Elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen ("ETA"), ETV6-AML1 fusion protein, EZH2, FGF5, FLT3-ITD, FNl, G250/MN/CAIX, GAGE-1,2,8, GAGE-3,4,5,6,7, GAS7, glypican-3, GnTV, gpl00/Pmell7, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL, HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDOl, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kalhkrein 4, KIF20A, KK-LC-1, KKLC1, KM-HN-1, KMHN1 also known as CCDCl lO, LAGE-1, LDLR-fucosyltransferaseAS fusion protein, Lengsin, M-CSF, MAGE-Al, MAGE-Al 0, MAGE-Al 2, MAGE-A2, MAGE- A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MCIR, MCSP, mdm-2, MEl, Melan- A/MART- 1 , Meloe, Midkine, MMP-2, MMP-7, MUCl, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88-A, neo-PAP, NFYC, NY- BR-1, NY-ESO-l/LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml- RARalpha fusion protein, polymorphic epithelial mucin ("PEM"), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB38/NY-MEL- 1 , RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, secernin 1, SIRT2, SNRPDl, SOX10, Spl7, SPA17, SSX-2, SSX-4, STEAPl, survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Tnosephosphate isomerase, TRP-l/gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1 and XAGE- 1 b/ GAGED2a.

168. The method of claim 166, wherein the cancer-associated antigen is a neo-antigen.

169. The method of any one of claim 166 to 168 wherein the polypeptide is a fusion protein.

170. The method of claim 165, wherein the cancer vaccine comprises a nucleic acid encoding an epitope of a cancer-associated antigen.

171. The method of claim 170, wherein the cancer-associated antigen is selected from the group consisting of adipophilin, AIM-2, ALDH1A1, alpha-actinin-4, alpha-fetoprotein ("AFP"), ARTCl, B-RAF, BAGE-1, BCLX (L), BCR-ABL fusion protein b3a2, beta-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin Dl, Cyclin-Al, dek-can fusion protein, DKK1, EFTUD2, Elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen ("ETA"), ETV6-AML1 fusion protein, EZH2, FGF5, FLT3-ITD, FNl, G250/MN/CAIX, GAGE-1,2,8, GAGE-3,4,5,6,7, GAS7, glypican-3, GnTV, gpl00/Pmell7, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL, HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDOl, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kalhkrein 4, KIF20A, KK-LC-1, KKLC1, KM-HN-1, KMHN1 also known as CCDCl lO, LAGE-1, LDLR-fucosyltransferaseAS fusion protein, Lengsin, M-CSF, MAGE-Al, MAGE-Al 0, MAGE-Al 2, MAGE-A2, MAGE- A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MCIR, MCSP, mdm-2, MEl, Melan- A/MART- 1 , Meloe, Midkine, MMP-2, MMP-7, MUCl, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88-A, neo-PAP, NFYC, NY- BR-1, NY-ESO-l/LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml- RARalpha fusion protein, polymorphic epithelial mucin ("PEM"), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB38/NY-MEL- 1 , RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, secernin 1, SIRT2, SNRPDl, SOX10, Spl7, SPA17, SSX-2, SSX-4, STEAPl, survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Tnosephosphate isomerase, TRP-l/gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1 and XAGE- 1 b/ GAGED2a.

172. The method of claim 170, wherein the cancer-associated antigen is a neo-antigen.

173. The method of any one of claims 170 to 172, wherein the nucleic acid is DNA.

174. The method of any one of claims 170 to 172, wherein the nucleic acid is RNA.

175. The method of claim 174, wherein the RNA is mRNA.

176. The method of any one of claims 170 to 175, wherein the nucleic acid is in a vector.

177. The method of claim 176, wherein the vector is a bacterial vector.

178. The method of claim 177, wherein the bacterial vector is selected from the group consisting of Mycobacterium bovis (BCG), Salmonella Typhimurium ssp., Salmonella Typhi ssp., Clostridium sp. spores, Escherichia coli Nissle 1917, Escherichia coli K-12/LLO, Listeria monocytogenes, and Shigella flexneri.

179. The method of claim 176, wherein the vector is a viral vector.

180. The method of claim 179, wherein the viral vector is selected from the group consisting of vaccinia, adenovirus, RNA viruses, and replication-defective avipox, replication-defective fowlpox, replication-defective canarypox, replication-defective MVA and replication-defective adenovirus.

181. The method any one of claims 155 to 180, wherein the cancer immunotherapy comprises administration of an antigen presenting cell (APC) primed with a cancer-specific antigen.

182. The method of claim 181, wherein the APC is a dendritic cell, a macrophage or a B cell.

183. The method of claim or claim 182, wherein the cancer-associated antigen is selected from the group consisting of adipophilin, AIM-2, ALDHlAl, alpha-actinin-4, alpha-fetoprotein ("AFP"), ARTCl, B-RAF, BAGE-1, BCLX (L), BCR-ABL fusion protein b3a2, beta-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin Dl, Cyclin-Al, dek-can fusion protein, DKK1, EFTUD2, Elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen ("ETA"), ETV6-AML1 fusion protein, EZH2, FGF5, FLT3-ITD, FNl, G250/MN/CAIX, GAGE-1,2,8, GAGE-3,4,5,6,7, GAS 7, glypican-3, GnTV, gpl00/Pmell7, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K- MEL, HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDOl, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kallikrein 4, KIF20A, KK-LC-1, KKLC1, KM-HN-1, KMHN1 also known as CCDC110, LAGE-1, LDLR-fucosyltransferaseAS fusion protein, Lengsin, M-CSF, MAGE-Al, MAGE- A 10, MAGE-A12, MAGE-A2, MAGE- A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-Cl, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MCIR, MCSP, mdm-2, ME1, Melan- A/MART- 1 , Meloe, Midkine, MMP-2, MMP-7, MUCl,

MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88-A, neo- PAP, NFYC, NY-BR-1, NY-ESO-l/LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml-RARalpha fusion protein, polymorphic epithelial mucin ("PEM"), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB38/NY-MEL- 1 , RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, secernin 1, SIRT2, SNRPDl, SOX10, Spl7, SPA17, SSX-2, SSX-4, STEAPl, survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Triosephosphate isomerase, TRP-l/gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1 and XAGE- 1 b/ GAGED2a.

184. The method of claim 181 or 182, wherein the cancer-associated antigen is a neo-antigen.

185. The method any one of claims 155 to 184, wherein the cancer immunotherapy comprises administration of a cancer-specific chimeric antigen receptor (CAR).

186. The method of claim 185, wherein the CAR is administered on the surface of a T cell.

187. The method of claim 185 or 186, wherein the CAR binds specifically to a cancer- associated antigen.

188. The method of claim 187, wherein the cancer-associated antigen is selected from the group consisting of adipophilin, AIM-2, ALDH1A1, alpha-actinin-4, alpha-fetoprotein ("AFP"), ARTCl, B-RAF, BAGE-1, BCLX (L), BCR-ABL fusion protein b3a2, beta-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin Dl, Cyclin-Al, dek-can fusion protein, DKK1, EFTUD2, Elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen ("ETA"), ETV6-AML1 fusion protein, EZH2, FGF5, FLT3-ITD, FNl, G250/MN/CAIX, GAGE-1,2,8, GAGE-3,4,5,6,7, GAS7, glypican-3, GnTV, gpl00/Pmell7, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL, HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDOl, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kallikrein 4, KIF20A, KK-LC-1, KKLC1, KM-HN-1, KMHN1 also known as CCDCl lO, LAGE-1, LDLR-fucosyltransferaseAS fusion protein, Lengsin, M-CSF, MAGE-Al, MAGE-Al 0, MAGE-Al 2, MAGE-A2, MAGE- A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MCIR, MCSP, mdm-2, MEl, Melan- A/MART- 1 , Meloe, Midkine, MMP-2, MMP-7, MUCl, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88-A, neo-PAP, NFYC, NY- BR-1, NY-ESO-l/LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml- RARalpha fusion protein, polymorphic epithelial mucin ("PEM"), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB38/NY-MEL- 1 , RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, secernin 1, SIRT2, SNRPDl, SOX10, Spl7, SPA17, SSX-2, SSX-4, STEAP1, survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Tnosephosphate isomerase, TRP-l/gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1 and XAGE- 1 b/ GAGED2a.

189. The method of claim 187, wherein the cancer associated antigen is a neo-antigen.

190. The method any one of claims 155 to 189, wherein the cancer immunotherapy comprises administration of a cancer-specific T cell to the subject.

191. The method of claim 190, wherein the T cell is a CD4+ T cell.

192. The method of claim 191, wherein the CD4+ T cell is a THI T cell, a TH2 T cell or a TH17 T cell.

193. The method of any one of claims 190 to 192, wherein the T cell expresses a T cell receptor specific for a cancer-associated antigen.

194. The method of claim 193, wherein the cancer-associated antigen is selected from the group consisting of adipophilin, AIM-2, ALDH1A1, alpha-actinin-4, alpha-fetoprotein ("AFP"), ARTC1, B-RAF, BAGE-1, BCLX (L), BCR-ABL fusion protein b3a2, beta-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin Dl, Cyclin-Al, dek-can fusion protein, DKK1, EFTUD2, Elongation factor 2, EN AH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen ("ETA"), ETV6-AML1 fusion protein, EZH2, FGF5, FLT3-ITD, FNl, G250/MN/CAIX, GAGE-1,2,8, GAGE-3,4,5,6,7, GAS7, glypican-3, GnTV, gpl00/Pmell7, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL, HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDOl, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kalhkrein 4, KIF20A, KK-LC-1, KKLC1, KM-HN-1, KMHN1 also known as CCDC110, LAGE-1, LDLR-fucosyltransferaseAS fusion protein, Lengsin, M-CSF, MAGE-A1, MAGE- A 10, MAGE-A12, MAGE-A2, MAGE- A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-Cl, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MCIR, MCSP, mdm-2, MEl, Melan- A/MART- 1 , Meloe, Midkine, MMP-2, MMP-7, MUCl, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88-A, neo-PAP, NFYC, NY- BR-1, NY-ESO-l/LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml- RARalpha fusion protein, polymorphic epithelial mucin ("PEM"), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB38/NY-MEL- 1 , RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, secernin 1, SIRT2, SNRPDl, SOX10, Spl7, SPA17, SSX-2, SSX-4, STEAPl, survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Tnosephosphate isomerase, TRP-l/gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1 and XAGE- 1 b/ GAGED2a.

195. The method of any one of claims 155 to 194, wherein the cancer immunotherapy comprises administration of an immune modulatory protein to the subject.

196. The method of claim 195, wherein the immune modulatory protein is a cytokine.

197. The method of claim 196, wherein the immune modulatory protein is selected from the group consisting of B lymphocyte chemoattractant ("BLC"), C-C motif chemokine 11 ("Eotaxin- 1"), Eosinophil chemotactic protein 2 ("Eotaxin-2"), Granulocyte colony-stimulating factor ("G- CSF"), Granulocyte macrophage colony-stimulating factor ("GM-CSF"), 1-309, Intercellular Adhesion Molecule 1 ("ICAM-1 "), Interferon gamma ("IFN-gamma"), Interlukin-1 alpha ("IL-1 alpha"), Interlukin-1 beta ("IL-1 beta"), Interleukin 1 receptor antagonist ("IL-1 ra"), Interleukin- 2 ("IL-2"), Interleukin-4 ("IL-4"), Interleukin-5 ("IL-5"), Interleukin-6 ("IL-6"), Interleukin-6 soluble receptor ("IL-6 sR"), Interleukin-7 ("IL-7"), Interleukin-8 ("IL-8"), Interleukin- 10 ("IL- 10"), Interleukin- 11 ("IL-l l "), Subumt beta of Interleukin- 12 ("IL-12 p40" or "IL-12 p70"), Interleukin- 13 ("IL-13"), Interleukin- 15 ("IL-15"), Interleukin- 16 ("IL-16"), Interleukin- 17 ("IL- 17"), Chemokine (C-C motif) Lignad 2 ("MCP-1"), Macrophage colony-stimulating factor ("M- CSF"), Monokine induced by gamma interferon ("MIG"), Chemokine (C-C motif) ligand 2 ("MIP-1 alpha"), Chemokine (C-C motif) ligand 4 ("MIP-1 beta"), Macrophage inflammatory protein- 1 -delta ("MIP-1 delta"), Platelet-derived growth factor subumt B ("PDGF-BB"), Chemokine (C-C motif) ligand 5, Regulated on Activation, Normal T cell Expressed and Secreted ("RANTES"), TIMP metallopeptidase inhibitor 1 ("ΉΜΡ-1 "), ΉΜΡ metallopeptidase inhibitor 2 ("TIMP-2"), Tumor necrosis factor, lymphotoxin-alpha ("TNF alpha"), Tumor necrosis factor, lymphotoxin-beta ("TNF beta"), Soluble TNF receptor type 1 ("sTNFRI"), sTNFRIIAR, Brain-derived neurotrophic factor ("BDNF"), Basic fibroblast growth factor ("bFGF"), Bone morphogenetic protein 4 ("BMP-4"), Bone morphogenetic protein 5 ("BMP-5"), Bone morphogenetic protein 7 ("BMP-7"), Nerve growth factor ("b-NGF"), Epidermal growth factor ("EGF"), Epidermal growth factor receptor ("EGFR"), Endocrine-gland-derived vascular endothelial growth factor ("EG-VEGF"), Fibroblast growth factor 4 ("FGF-4"), Keratinocyte growth factor ("FGF-7"), Growth differentiation factor 15 ("GDF-15"), Glial cell-derived neurotrophic factor ("GDNF"), Growth Hormone, Heparin-binding EGF-like growth factor ("HB-EGF"), Hepatocyte growth factor ("HGF"), Insulin-like growth factor binding protein 1 ("IGFBP-l"), Insulin-like growth factor binding protein 2 ("IGFBP-2"), Insulin-like growth factor binding protein 3 (" IGFBP-3"), Insulin-like growth factor binding protein 4 ("IGFBP-4"), Insulin-like growth factor binding protein 6 ("IGFBP-6"), Insulin-like growth factor 1 ("IGF-l"), Insulin, Macrophage colony-stimulating factor ("M-CSF R"), Nerve growth factor receptor ("NGF R"), Neurotrophin-3 ("NT-3"), Neurotrophin-4 ("NT-4"), Osteoclastogenesis inhibitory factor ("Osteoprotegerin"), Platelet-derived growth factor receptors ("PDGF-AA"),

Phosphatidylinositol-glycan biosynthesis ("PIGF"), Skp, Cullin, F-box containing complex ("SCF"), Stem cell factor receptor ("SCF R"), Transforming growth factor alpha ("TGFalpha"), Transforming growth factor beta-1 ("TGF beta 1"), Transforming growth factor beta-3 ("TGF beta 3"), Vascular endothelial growth factor ("VEGF"), Vascular endothelial growth factor receptor 2 ("VEGFR2"), Vascular endothelial growth factor receptor 3 ("VEGFR3"), VEGF-D 6Ckine, Tyrosine-protein kinase receptor UFO ("Axl"), Betacellulin ("BTC"), Mucosae- associated epithelial chemokine ("CCL28"), Chemokine (C-C motif) ligand 27 ("CTACK"), Chemokine (C-X-C motif) ligand 16 ("CXCL16"), C-X-C motif chemokine 5 ("ENA-78"), Chemokine (C-C motif) ligand 26 ("Eotaxin-3"), Granulocyte chemotactic protein 2 ("GCP-2"), GRO, Chemokine (C-C motif) ligand 14 ("HCC-l"), Chemokine (C-C motif) ligand 16 ("HCC- 4"), Interleukin-9 ("IL-9"), Interleukin-17 F ("IL-17F"), Interleukin- 18-binding protein ("IL-18 BPa"), Interleukin-28 A ("IL-28A"), Interleukin 29 ("IL-29"), Interleukin 31 ("IL-31 "), C-X-C motif chemokine 10 ("IP-10"), Chemokine receptor CXCR3 ("I-TAC"), Leukemia inhibitory factor ("LIF"), Light, Chemokine (C motif) ligand ("Lymphotactin"), Monocyte chemoattractant protein 2 ("MCP-2"), Monocyte chemoattractant protein 3 ("MCP-3"), Monocyte

chemoattractant protein 4 ("MCP-4"), Macrophage-derived chemokine ("MDC"), Macrophage migration inhibitory factor ("MIF"), Chemokine (C-C motif) ligand 20 ("MIP-3 alpha"), C-C motif chemokine 19 ("MIP-3 beta"), Chemokine (C-C motif) ligand 23 ("MPIF-1 "), Macrophage stimulating protein alpha chain ("MSPalpha"), Nucleosome assembly protein 1-like 4 ("NAP- 2"), Secreted phosphoprotein 1 ("Osteopontin"), Pulmonary and activation-regulated cytokine ("PARC"), Platelet factor 4 ("PF4"), Stroma cell-derived factor- 1 alpha ("SDF-1 alpha"), Chemokine (C-C motif) ligand 17 ("TARC"), Thymus-expressed chemokine ("TECK"), Thymic stromal lymphopoietin ("TSLP 4- IBB"), CD 166 antigen ("ALCAM"), Cluster of Differentiation 80 ("B7-1 "), Tumor necrosis factor receptor superfamily member 17 ("BCMA"), Cluster of Differentiation 14 ("CD14"), Cluster of Differentiation 30 ("CD30"), Cluster of Differentiation 40 ("CD40 Ligand"), Carcinoembryonic antigen-related cell adhesion molecule 1 (biliary glycoprotein) ("CEACAM-1 "), Death Receptor 6 ("DR6"), Deoxythymidine kinase ("Dtk"), Type 1 membrane glycoprotein ("Endoglin"), Receptor tyrosine-protein kinase erbB-3

("ErbB3"), Endothelial-leukocyte adhesion molecule 1 ("E-Selectin"), Apoptosis antigen 1 ("Fas"), Fms-like tyrosine kinase 3 ("Flt-3L"), Tumor necrosis factor receptor superfamily member 1 ("GITR"), Tumor necrosis factor receptor superfamily member 14 ("HVEM"), Intercellular adhesion molecule 3 ("ICAM-3"), IL-1 R4, IL-1 RI, IL-10 Rbeta, IL-17R, IL- 2Rgamma, IL-21R, Lysosome membrane protein 2 ("LIMPII"), Neutrophil gelatinase-associated hpocalin ("Lipocalin-2"), CD62L ("L-Selectin"), Lymphatic endothelium ("LYVE-1"), MHC class I polypeptide-related sequence A ("MICA"), MHC class I polypeptide-related sequence B ("MICB"), NRGl-betal, Beta-type platelet-derived growth factor receptor ("PDGF Rbeta"), Platelet endothelial cell adhesion molecule ("PECAM-1"), RAGE, Hepatitis A virus cellular receptor 1 ("ΉΜ-1"), Tumor necrosis factor receptor superfamily member IOC ("TRAIL R3"), Trappin protein transglutaminase binding domain ("Trappin-2"), Urokinase receptor ("uPAR"), Vascular cell adhesion protein 1 ("VCAM-1"), XEDARActivin A, Agouti-related protein ("AgRP"), Ribonuclease 5 ("Angiogenin"), Angiopoietin 1, Angiostatin, Catheprin S, CD40, Cryptic family protein IB ("Cripto-1"), DAN, Dickkopf-r elated protein 1 ("DKK-1"), E- Cadherin, Epithelial cell adhesion molecule ("EpCAM"), Fas Ligand (FasL or CD95L), Fcg RIIB/C, FoUistatin, Galectin-7, Intercellular adhesion molecule 2 ("ICAM-2"), IL-13 Rl, IL- 13R2, IL-17B, IL-2 Ra, IL-2 Rb, IL-23, LAP, Neuronal cell adhesion molecule ("NrCAM"), Plasminogen activator inhibitor- 1 ("PAI-1"), Platelet derived growth factor receptors ("PDGF- AB"), Resistin, stromal cell-derived factor 1 ("SDF-1 beta"), sgpl30, Secreted frizzled-related protein 2 ("ShhN"), Sialic acid-binding immunoglobulin-type lectins ("Siglec-5"), ST2, Transforming growth factor-beta 2 ("TGF beta 2"), Tie-2, Thrombopoietin ("TPO"), Tumor necrosis factor receptor superfamily member 10D ("TRAIL R4"), Triggering receptor expressed on myeloid cells 1 ("TREM-1"), Vascular endothelial growth factor C ("VEGF-C"),

VEGFRlAdiponectin, Adipsin ("AND"), Alpha-fetoprotein ("AFP"), Angiopoietin-like 4 ("ANGPTL4"), Beta-2-microglobulin ("B2M"), Basal cell adhesion molecule ("BCAM"), Carbohydrate antigen 125 ("CA125"), Cancer Antigen 15-3 ("CA15-3"), Carcinoembryonic antigen ("CEA"), cAMP receptor protein ("CRP"), Human Epidermal Growth Factor Receptor 2 ("ErbB2"), Follistatin, Follicle-stimulating hormone ("FSH"), Chemokine (C-X-C motif) ligand 1 ("GRO alpha"), human chorionic gonadotropin ("beta HCG"), Insulin-like growth factor 1 receptor ("IGF-l sR"), IL-1 sRII, IL-3, IL-18 Rb, IL-21, Leptin, Matrix metalloproteinase-1 ("MMP-1 "), Matrix metalloproteinase-2 ("MMP-2"), Matrix metalloproteinase-3 ("MMP-3"), Matrix metalloproteinase-8 ("MMP-8"), Matrix metalloproteinase-9 ("MMP-9"), Matrix metalloproteinase-10 ("MMP-10"), Matrix metalloproteinase-13 ("MMP-13"), Neural Cell Adhesion Molecule ("NCAM-1"), Entactin ("Nidogen-1 "), Neuron specific enolase ("NSE"), Oncostatin M ("OSM"), Procalcitonin, Prolactin, Prostate specific antigen ("PSA"), Sialic acid- binding Ig-like lectin 9 ("Siglec-9"), ADAM 17 endopeptidase ("TACE"), Thyroglobulm, Metalloproteinase inhibitor 4 ("TIMP-4"), TSH2B4, Disintegrin and metalloproteinase domain- containing protein 9 ("ADAM-9"), Angiopoietin 2, Tumor necrosis factor ligand superfamily member 13/ Acidic leucine-rich nuclear phosphoprotein 32 family member B ("APRIL"), Bone morphogenetic protein 2 ("BMP-2"), Bone morphogenetic protein 9 ("BMP-9"), Complement component 5a ("C5a"), Cathepsin L, CD200, CD97, Chemerin, Tumor necrosis factor receptor superfamily member 6B ("DcR3"), Fatty acid-binding protein 2 ("FABP2"), Fibroblast activation protein, alpha ("FAP"), Fibroblast growth factor 19 ("FGF-19"), Galectin-3, Hepatocyte growth factor receptor ("HGF R"), IFN-gammalpha/beta R2, Insulin-like growth factor 2 ("IGF-2"), Insulin-like growth factor 2 receptor ("IGF-2 R"), Interleukin- 1 receptor 6 ("IL-1R6"),

Interleukin 24 ("IL-24"), Interleukin 33 ("IL-33", Kallikrein 14, Asparaginyl endopeptidase ("Legumain"), Oxidized low-density lipoprotein receptor 1 ("LOX-1"), Mannose-binding lectin ("MBL"), Neprilysin ("NEP"), Notch homolog 1, translocation-associated (Drosophila) ("Notch- 1"), Nephroblastoma overexpressed ("NOV"), Osteoactivin, Programmed cell death protein 1 ("PD-1 "), N-acetylmuramoyl-L-alanine amidase ("PGRP-5"), Serpin A4, Secreted frizzled related protein 3 ("sFRP-3"), Thrombomodulin, Tolllike receptor 2 ("TLR2"), Tumor necrosis factor receptor superfamily member 10A ("TRAIL Rl"), Transferrin ("TRF"), WIF-lACE-2, Albumin, AMICA, Angiopoietin 4, B-cell activating factor ("BAFF"), Carbohydrate antigen 19- 9 ("CA19-9"), CD 163 , Clusterin, CRT AM, Chemokine (C-X-C motif) ligand 14 ("CXCL14"), Cystatin C, Decorin ("DCN"), Dickkopf-related protein 3 ("Dkk-3"), Delta-like protein 1 ("DLL1 "), Fetuin A, Heparin-binding growth factor 1 ("aFGF"), Folate receptor alpha

("FOLR1"), Funn, GPCR-associated sorting protein 1 ("GASP-1"), GPCR-associated sorting protein 2 ("GASP-2"), Granulocyte colony- stimulating factor receptor ("GCSF R"), Serine protease hepsin ("HAI-2"), Interleukin- 17B Receptor ("IL-17B R"), Interleukin 27 ("IL-27"), Lymphocyte-activation gene 3 ("LAG-3"), Apolipoprotein A-V ("LDL R"), Pepsinogen I, Retinol binding protein 4 ("RBP4"), SOST, Heparan sulfate proteoglycan ("Syndecan-1"), Tumor necrosis factor receptor superfamily member 13B ("TACI"), Tissue factor pathway inhibitor ("TFPI"), TSP-1, Tumor necrosis factor receptor superfamily, member 10b ("TRAIL R2"), TRANCE, Troponin I, Urokinase Plasminogen Activator ("uPA"), Cadherin 5, type 2 or VE-cadherin (vascular endothelial) also known as CD144 ("VE-Cadherin"), WNTl-inducible- signaling pathway protein 1 ("WISP-1 "), and Receptor Activator of Nuclear Factor κ B

("RANK").

198. The method of any one of claims 155 to 197, wherein the cancer immunotherapy comprises administering an adjuvant to the subject.

199. The method of claim 198, wherein the adjuvant is selected from the group consisting of an immune modulatory protein, Adjuvant 65, a-GalCer, aluminum phosphate, aluminum hydroxide, calcium phosphate, β-Glucan Peptide, CpG DNA, GPI-0100, lipid A,

lipopolysaccharide, Lipovant, Montanide, N-acetyl-muramyl-L-alanyl-D-isoglutamine, Pam3CSK4, quil A and trehalose dimycolate.

200. The method of any one of claims 152 to 199, wherein second the cancer therapy comprises administering an angiogenesis inhibitor to the subject.

201. The method of claim 200, wherein the angiogenesis inhibitor is selected from the group consisting of Bevacizumab (Avastin®), Ziv-aflibercept (Zaltrap®), Sorafenib (Nexavar®), Sunitinib (Sutent®), Pazopanib (Votrient®), Regorafenib (Stivarga®), and Cabozantinib (Cometnq™).

202. The method of any one of claims 152 to 201, wherein the cancer therapy comprises radiation therapy.

203. The method of any one of claims 126 to 202, wherein the method further comprises administering an antibiotic to the subject.

204. The method of claim 203, wherein the antibiotic is selected from the group consisting of aminoglycosides, ansamycins, carbacephems, carbapenems, cephalosporins, glycopeptides, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, oxazolidonones, penicillins, polypeptide antibiotics, quinolones, fluoroquinolone, sulfonamides, tetracyclines, anti- mycobacterial compounds and combinations thereof.

205. The method of any one of claims 126 to 204, wherein the cancer therapy comprises administering to the subject a second therapeutic bacteria.

206. The method of any one of claims 126 to 204, wherein the method further comprises administering a prebiotic to the subject.

207. The method of claim 206, wherein the prebiotic is a fructooligosaccharide, a galactooligosaccharide, a trans-galactooligosaccharide, a xylooligosaccharide, a

chitooligosaccharide, a soy oligosaccharides, a gentiooligosaccharide, an

isomaltooligosaccharide, a mannooligosaccharide, a maltooligosaccharide, a mannanoligosaccharide, lactulose, lactosucrose, palatinose, glycosyl sucrose, guar gum, gum Arabic, tagalose, amylose, amylopectin, pectin, xylan, or a cyclodextrin.

208. The method of any one of claims 126 to 207, wherein the subject is a human.

209. The method of any one of claims 126 to 207, wherein the subject is a non-human mammal.

210. The method of claim 209, wherein the mammal is selected from the group consisting of a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a guinea pig, a sheep, a llama, a monkey, a gorilla or a chimpanzee.

Description:
IDENTIFICATION OF BACTERIA FOR CANCER THERAPY RELATED APPLICATIONS

[1] This application claims the benefit of priority to U.S. Provisional Patent Application having serial number 62/572,139, filed October 13, 2017, the contents of which is hereby incorporated herein by reference in its entirety. SUMMARY

[2] In certain aspects, provided herein is a method for identifying bacteria (e.g., bacteria of a genus, species or strain listed in Table 1, Table 2 and/or Table 3) as being a likely cancer therapeutic. In some embodiments, the method comprises culturing the bacteria with immune cells (e.g., peripheral blood mononuclear cells (PBMCs), macrophages, dendritic cells). In certain embodiments, the method comprises detecting whether the bacteria modulates expression of one or more cytokines by the immune cells (e.g., whether the expression of the one or more cytokines by the immune cells cultured with the bacteria is higher or lower than the expression of the one or more cytokines by the same type of immune cells cultured in the absence of the bacteria and/or cultured with a control bacteria strain that is not therapeutically effective for the treatment of cancer). In certain embodiments, the method further comprises identifying the bacteria as being a likely cancer therapeutic based on the expression of the one or more cytokines. In certain embodiments, the method further comprises subjecting the bacteria identified as a likely cancer therapeutic to further assays (e.g., in vivo non-human animal cancer model assays) to further validate the likely cancer therapeutic. In some embodiments, the likely cancer therapeutic is administered to a human who has cancer.

[3] In certain embodiments, the immune cell is a cell capable of expressing the cytokine IP- 10 (also referred to as CXCL10). In some embodiments, the method comprises detecting IP-10 expression by the immune cells (e.g., detecting the presence of IP-10 mRNA and/or IP-10 protein in the cells and/or culture media). In some embodiments, if the bacteria induces expression of IP-10 in the immune cells (e.g., causes the immune cells cultured with the bacteria to express at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold or 100-fold more IP-10 then the same type of immune cells cultured in the absence of the bacteria and/or cultured with a control bacteria strain that is not therapeutically effective for the treatment of cancer) the bacteria are identified as a likely cancer therapeutic.

[4] In certain embodiments, the immune cell is a cell capable of expressing the cytokines IP- 10 and IL-10. In some embodiments, the method comprises detecting IP-10 expression by the immune cells (e.g., detecting the presence of IP-10 mRNA and/or IP-10 protein in the cells and/or culture media) and detecting IL-10 expression by the immune cells (e.g., detecting the presence of IL-10 mRNA and/or IL-10 protein in the cells and/or culture media). In some embodiments, if the bacteria induces the immune cells to express an elevated ratio of IP-10 to IL-10 (e.g., causes the immune cells to express a ratio of IP-10:IL-10 that is at least 2-fold, 3- fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35- fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold or 100-fold higher than the ratio expressed by the same type of immune cells cultured in the absence of the bacteria and/or cultured with a control bacteria strain that is not therapeutically effective for the treatment of cancer) the bacteria are identified as a likely cancer therapeutic.

[5] In certain embodiments, the immune cell is a cell capable of expressing the cytokines IP- 10 and GM-CSF. In some embodiments, the method comprises detecting IP-10 expression by the immune cells (e.g., detecting the presence of IP-10 mRNA and/or IP-10 protein in the cells and/or culture media) and detecting GM-CSF expression by the immune cells (e.g., detecting the presence of GM-CSF mRNA and/or GM-CSF protein in the cells and/or culture media). In some embodiments, if the bacteria induces the immune cells to express an elevated ratio of IP-10 to GM-CSF (e.g., causes the immune cells to express a ratio of IP-10: GM-CSF that is at least 2- fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30- fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold or 100-fold higher than the ratio expressed by the same type of immune cells cultured in the absence of the bacteria and/or cultured with a control bacteria strain that is not therapeutically effective for the treatment of cancer) the bacteria are identified as a likely cancer therapeutic.

[6] In certain aspects, provided herein are therapeutic bacteria that induce expression of IP- 10 (e.g., bacteria that induce expression of IP10 in an assay provided herein). In certain aspects, provided herein are therapeutic bacteria that induce an elevated ratio of IP-10:IL-10 expression (e.g., bacteria that induce an elevated ratio of IP-10:IL-10 expression in an assay provided herein). In certain aspects, provided herein are therapeutic bacteria that induce an elevated ratio of IP-10:GM-CSF expression (e.g., bacteria that induce an elevated ratio of IP-10:GM-CSF expression in an assay provided herein). In certain embodiments, the bacteria are of a genus, species or strain listed in Table 1, Table 2 and/or Table 3.

[7] In some embodiments, the therapeutic bacteria provided herein are engineered bacteria that is modified to enhance certain desirable properties. For example, in some embodiments, the bacteria are engineered to induce expression of IP-10 in immune cells. In some embodiments, the bacteria are engineered to induce an elevated ratio of IP-10:IL-10 expression and/or IP-10:GM- CSF expression in immune cells. In some embodiments, the engineered bacteria are modified to improve oral delivery (e.g., by improving acid resistance, muco-adherence and/or penetration and/or resistance to bile acids, resistance to anti-microbial peptides and/or antibody

neutralization), to target desired cell types (e.g. M-cells, goblet cells, enterocytes, dendritic cells, macrophages) to improve bioavailability systemically or in an appropriate niche (e.g., mesenteric lymph nodes, Peyer’s patches, lamina propria, tumor draining lymph nodes, and/or blood), to enhance their immunomodulatory and/or therapeutic effect (e.g., either alone or in combination with another therapeutic agent), to enhance immune activation and/or to improve bacterial manufacturing (e.g., greater stability, improved freeze-thaw tolerance, shorter generation times).

[8] In certain embodiments, provided herein are methods of treating a subject who has cancer comprising administering to the subject a pharmaceutical composition comprising the therapeutic bacteria described herein. In some embodiments, the method further comprises administering to the subject an antibiotic. In some embodiments, the method further comprises administering to the subject one or more other cancer therapies (e.g., surgical removal of a tumor, the

administration of a chemotherapeutic agent, the administration of radiation therapy, and/or the administration of a cancer immunotherapy, such as an immune checkpoint inhibitor, a cancer- specific antibody, a cancer vaccine, a primed antigen presenting cell, a cancer-specific T cell, a cancer-specific chimeric antigen receptor (CAR) T cell, an immune activating protein, and/or an adjuvant). In some embodiments, the method further comprises the administration of another therapeutic bacterium. BRIEF DESCRIPTION OF THE FIGURES [9] Figure 1 shows that human macrophages produce high levels of IP-10 and high ratios of IP-10 to IL-10 in response to therapeutically effective bacteria strains but not therapeutically ineffective bacteria strains.

[10] Figure 2 shows that human PBMCs produce high levels of IP-10 and high ratios of IP-10 to GM-CSF in response to therapeutically effective bacteria strains but not therapeutically ineffective bacteria strains.

[11] Figure 3 shows that in a mouse colorectal carcinoma model, the efficacy of orally administered Blautia Strain A compared to that of intraperitoneally (i.p.) administered anti-PD-1.

[12] Figure 4 shows inhibition of tumor growth (by volume) by the oral administration of Blautia Strain A compared to intraperitoneally (i.p.) administered anti-PD-1 in a mouse colorectal carcinoma model.

[13] Figure 5 shows that in a mouse melanoma model, the efficacy of orally administered Blautia Strain A is comparable to that of intraperitoneally (i.p.) administered anti-PD-L1.

[14] Figure 6 shows inhibition of tumor growth (by volume) by the oral administration of Blautia Strain A compared to intraperitoneally (i.p.) administered anti-PD-L1 in a mouse melanoma model.

[15] Figure 7 shows inhibition of tumor growth (by volume) by the oral administration of Bifidobacterium animalis ssp. lactis Strain A in a mouse colorectal carcinoma model.

[16] Figure 8 shows that in a mouse colorectal carcinoma model, the efficacy of orally administered Bifidobacterium animalis ssp. lactis Strain A is comparable to that of

intraperitoneally (i.p.) administered anti-PD-1.

[17] Figure 9 shows that in a mouse colorectal carcinoma model, the efficacy of

intratumorally Bifidobacterium animalis ssp. lactis Strain A is comparable to that of

intraperitoneally (i.p.) administered anti-PD-1.

[18] Figure 10 shows that human macrophages produce higher ratios of IP-10 to IL-10 in response to therapeutically effective bacteria strains (Paraclostridium benzoelyticum,

Agathobaculum sp, and Turicibacter sanguinis) but not in response to therapeutically ineffective bacteria strains (Bacteroides ovatus (Strain Y) and Clostridium symbiosum (Strain Z)). DETAILED DESCRIPTION

Definitions [19] “Adjuvant” or“Adjuvant therapy” broadly refers to an agent that affects an immunological or physiological response in a patient or subject. For example, an adjuvant might increase the presence of an antigen over time or to an area of interest like a tumor, help absorb an antigen presenting cell antigen, activate macrophages and lymphocytes and support the production of cytokines. By changing an immune response, an adjuvant might permit a smaller dose of an immune interacting agent to increase the effectiveness or safety of a particular dose of the immune interacting agent. For example, an adjuvant might prevent T cell exhaustion and thus increase the effectiveness or safety of a particular immune interacting agent.

[20] “Administration” broadly refers to a route of administration of a composition to a subject. Examples of routes of administration include oral administration, rectal administration, topical administration, inhalation (nasal) or injection. Administration by injection includes intravenous (IV), intramuscular (IM), intratumoral (IT) and subcutaneous (SC) administration. The pharmaceutical compositions described herein can be administered in any form by any effective route, including but not limited to intratumoral, oral, parenteral, enteral, intravenous,

intraperitoneal, topical, transdermal (e.g., using any standard patch), intradermal, ophthalmic, (intra)nasally, local, non-oral, such as aerosol, inhalation, subcutaneous, intramuscular, buccal, sublingual, (trans)rectal, vaginal, intra-arterial, and intrathecal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), implanted, intravesical, intrapulmonary, intraduodenal, intragastrical, and intrabronchial. In preferred embodiments, the pharmaceutical compositions described herein are administered orally, rectally, intratumorally, topically, intravesically, by injection into or adjacent to a draining lymph node, intravenously, by inhalation or aerosol, or subcutaneously.

[21] As used herein, the term“antibody” may refer to both an intact antibody and an antigen binding fragment thereof. Intact antibodies are glycoproteins that include at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain includes a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. Each light chain includes a light chain variable region (abbreviated herein as VL) and a light chain constant region. The VH and VL regions can be further subdivided into regions of

hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each V H and V L is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The term“antibody” includes, for example, monoclonal antibodies, polyclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, multispecific antibodies (e.g., bispecific antibodies), single-chain antibodies and antigen-binding antibody fragments.

[22] The terms“antigen binding fragment” and“antigen-binding portion” of an antibody, as used herein, refers to one or more fragments of an antibody that retain the ability to bind to an antigen. Examples of binding fragments encompassed within the term "antigen-binding fragment" of an antibody include Fab, Fab', F(ab')2, Fv, scFv, disulfide linked Fv, Fd, diabodies, single-chain antibodies, NANOBODIES®, isolated CDRH3, and other antibody fragments that retain at least a portion of the variable region of an intact antibody. These antibody fragments can be obtained using conventional recombinant and/or enzymatic techniques and can be screened for antigen binding in the same manner as intact antibodies.

[23] “Cancer” broadly refers to an uncontrolled, abnormal growth of a host’s own cells leading to invasion of surrounding tissue and potentially tissue distal to the initial site of abnormal cell growth in the host. Major classes include carcinomas which are cancers of the epithelial tissue (e.g., skin, squamous cells); sarcomas which are cancers of the connective tissue (e.g., bone, cartilage, fat, muscle, blood vessels, etc.); leukemias which are cancers of blood forming tissue (e.g., bone marrow tissue); lymphomas and myelomas which are cancers of immune cells; and central nervous system cancers which include cancers from brain and spinal tissue.“Cancer(s),”“neoplasm(s),” and“tumor(s)” are used herein interchangeably. As used herein, "cancer" refers to all types of cancer or neoplasm or malignant tumors including leukemias, carcinomas and sarcomas, whether new or recurring. Specific examples of cancers are: carcinomas, sarcomas, myelomas, leukemias, lymphomas and mixed type tumors. Non- limiting examples of cancers are new or recurring cancers of the brain, melanoma, bladder, breast, cervix, colon, head and neck, kidney, lung, non-small cell lung, mesothelioma, ovary, prostate, sarcoma, stomach, uterus and medulloblastoma.

[24] “Cellular augmentation” broadly refers to the influx of cells or expansion of cells in an environment that are not substantially present in the environment prior to administration of a composition and not present in the composition itself. Cells that augment the environment include immune cells, stromal cells, bacterial and fungal cells. Environments of particular interest are the microenvironments where cancer cells reside or locate. In some instances, the microenvironment is a tumor microenvironment or a tumor draining lymph node. In other instances, the microenvironment is a pre-cancerous tissue site or the site of local administration of a composition or a site where the composition will accumulate after remote administration.

[25] “Clade” refers to the OTUs or members of a phylogenetic tree that are downstream of a statistically valid node in a phylogenetic tree. The clade comprises a set of terminal leaves in the phylogenetic tree that is a distinct monophyletic evolutionary unit and that share some extent of sequence similarity.“Operational taxonomic units,”“OTU” (or plural,“OTUs”) refer to a terminal leaf in a phylogenetic tree and is defined by a nucleic acid sequence, e.g., the entire genome, or a specific genetic sequence, and all sequences that share sequence identity to this nucleic acid sequence at the level of species. In some embodiments the specific genetic sequence may be the 16S sequence or a portion of the 16S sequence. In other embodiments, the entire genomes of two entities are sequenced and compared. In another embodiment, select regions such as multilocus sequence tags (MLST), specific genes, or sets of genes may be genetically compared. In 16S embodiments, OTUs that share≧97% average nucleotide identity across the entire 16S or some variable region of the 16S are considered the same OTU (see e.g. Claesson M J, Wang Q, O'Sullivan O, Greene-Diniz R, Cole J R, Ros R P, and O'Toole P W.2010.

Comparison of two next-generation sequencing technologies for resolving highly complex microbiota composition using tandem variable 16S rRNA gene regions. Nucleic Acids Res 38: e200. Konstantinidis K T, Ramette A, and Tiedje J M.2006. The bacterial species definition in the genomic era. Philos Trans R Soc Lond B Biol Sci 361: 1929-1940.). In embodiments involving the complete genome, MLSTs, specific genes, or sets of genes OTUs that share≧95% average nucleotide identity are considered the same OTU (see e.g. Achtman M, and Wagner M. 2008. Microbial diversity and the genetic nature of microbial species. Nat. Rev. Microbiol.6: 431-440. Konstantinidis K T, Ramette A, and Tiedje J M.2006. The bacterial species definition in the genomic era. Philos Trans R Soc Lond B Biol Sci 361: 1929-1940.). OTUs are frequently defined by comparing sequences between organisms. Generally, sequences with less than 95% sequence identity are not considered to form part of the same OTU. OTUs may also be characterized by any combination of nucleotide markers or genes, in particular highly conserved genes (e.g.,“house-keeping” genes), or a combination thereof. Such characterization employs, e.g., WGS data or a whole genome sequence.

[26] The term“decrease” or“deplete” means a change, such that the difference is, depending on circumstances, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 1/100, 1/1000, 1/10,000, 1/100,000, 1/1,000,000 or undetectable after treatment when compared to a pre- treatment state.

[27] As used herein, the term“Dysbiosis” refers to a state in which the synergy between microbes and the tumor is broken such as the microbes no longer support the nucleation, maintenance, progression or spread or metastasis of a tumor.

[28] The term“epitope” means a protein determinant capable of specific binding to an antibody or T cell receptor. Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains. Certain epitopes can be defined by a particular sequence of amino acids to which an antibody is capable of binding.

[29] As used herein,“engineered bacteria” are any bacteria that have been genetically altered from their natural state by human intervention and the progeny of any such bacteria. Engineered bacteria include, for example, the products of targeted genetic modification, the products of random mutagenesis screens and the products of directed evolution.

[30] The term“gene” is used broadly to refer to any nucleic acid associated with a biological function. The term“gene” applies to a specific genomic sequence, as well as to a cDNA or an mRNA encoded by that genomic sequence.

[31] “Identity” as between nucleic acid sequences of two nucleic acid molecules can be determined as a percentage of identity using known computer algorithms such as the“FASTA” program, using for example, the default parameters as in Pearson et al. (1988) Proc. Natl. Acad. Sci. USA 85:2444 (other programs include the GCG program package (Devereux, J., et al., Nucleic Acids Research 12(I):387 (1984)), BLASTP, BLASTN, FASTA Atschul, S. F., et al., J Molec Biol 215:403 (1990); Guide to Huge Computers, Mrtin J. Bishop, ed., Academic Press, San Diego, 1994, and Carillo et al. (1988) SIAM J Applied Math 48:1073). For example, the BLAST function of the National Center for Biotechnology Information database can be used to determine identity. Other commercially or publicly available programs include, DNAStar “MegAlign” program (Madison, Wis.) and the University of Wisconsin Genetics Computer Group (UWG)“Gap” program (Madison Wis.)). [32] As used herein, the term“immune disorder” refers to any disease, disorder or disease symptom caused by an activity of the immune system, including autoimmune diseases, inflammatory diseases and allergies. Immune disorders include, but are not limited to, autoimmune diseases (e.g., Lupus, Scleroderma, hemolytic anemia, vasculitis, type one diabetes, Grave’s disease, rheumatoid arthritis, multiple sclerosis, Goodpasture’s syndrome, pernicious anemia and/or myopathy), inflammatory diseases (e.g., acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis and/or interstitial cystitis), and/or an allergies (e.g., food allergies, drug allergies and/or environmental allergies).

[33] “Immunotherapy” is treatment that uses a subject’s immune system to treat disease (e.g., immune disease, inflammatory disease, metabolic disease, cancer) and includes, for example, checkpoint inhibitors, cancer vaccines, cytokines, cell therapy, CAR-T cells, and dendritic cell therapy.

[34] The term“increase” means a change, such that the difference is, depending on circumstances, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 2-fold, 4-fold, 10- fold, 100-fold, 10^3 fold, 10^4 fold, 10^5 fold, 10^6 fold, and/or 10^7 fold greater after treatment when compared to a pre-treatment state. Properties that may be increased include immune cells, bacterial cells, stromal cells, myeloid derived suppressor cells, fibroblasts, metabolites, and cytokines.

[35] “Innate immune agonists” or“immuno-adjuvants” are small molecules, proteins, or other agents that specifically target innate immune receptors including Toll-Like Receptors, NOD receptors, RLRs, C-type lectin receptors, STING-cGAS Pathway components, inflammasome complexes. For example, LPS is a TLR-4 agonist that is bacterially derived or synthesized and aluminum can be used as an immune stimulating adjuvant. immuno-adjuvants are a specific class of broader adjuvant or adjuvant therapy.

[36] The“internal transcribed spacer” or“ ITS” is a piece of non-functional RNA located between structural ribosomal RNAs (rRNA) on a common precursor transcript often used for identification of eukaryotic species in particular fungi. The rRNA of fungi that forms the core of the ribosome is transcribed as a signal gene and consists of the 8S, 5.8S and 28S regions with ITS4 and 5 between the 8S and 5.8S and 5.8S and 28S regions, respectively. These two intercistronic segments between the 18S and 5.8S and 5.8S and 28S regions are removed by splicing and contain significant variation between species for barcoding purposes as previously described (Schoch et al Nuclear ribosomal internal transcribed spacer (ITS) region as a universal DNA barcode marker for Fungi. PNAS 109:6241-6246.2012).18S rDNA is traditionally used for phylogenetic reconstruction however the ITS can serve this function as it is generally highly conserved but contains hypervariable regions that harbor sufficient nucleotide diversity to differentiate genera and species of most fungus.

[37] The term“isolated” or“enriched” encompasses a microbe, EV or other entity or substance that has been (1) separated from at least some of the components with which it was associated when initially produced (whether in nature or in an experimental setting), and/or (2) produced, prepared, purified, and/or manufactured by the hand of man. Isolated microbes may be separated from at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more of the other components with which they were initially associated. In some embodiments, isolated microbes are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure. As used herein, a substance is“pure” if it is substantially free of other components. The terms“purify,”“purifying” and“purified” refer to a microbe or other material that has been separated from at least some of the components with which it was associated either when initially produced or generated (e.g., whether in nature or in an experimental setting), or during any time after its initial production. A microbe or a microbial population may be considered purified if it is isolated at or after production, such as from a material or environment containing the microbe or microbial population, and a purified microbe or microbial population may contain other materials up to about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or above about 90% and still be considered“isolated.” In some embodiments, purified microbes or microbial population are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure. In the instance of microbial compositions provided herein, the one or more microbial types present in the composition can be independently purified from one or more other microbes produced and/or present in the material or environment containing the microbial type. Microbial compositions and the microbial components thereof are generally purified from residual habitat products.“

[38] “Metabolite” as used herein refers to any and all molecular compounds, compositions, molecules, ions, co-factors, catalysts or nutrients used as substrates in any cellular or microbial metabolic reaction or resulting as product compounds, compositions, molecules, ions, co-factors, catalysts or nutrients from any cellular or microbial metabolic reaction.

[39] “Microbe” refers to any natural or engineered organism characterized as a bacterium, fungus, microscopic alga, protozoan, and the stages of development or life cycle stages (e.g., vegetative, spore (including sporulation, dormancy, and germination), latent, biofilm) associated with the organism. Examples of gut microbes include: Actinomyces graevenitzii, Actinomyces odontolyticus, Akkermansia muciniphila, Bacteroides caccae, Bacteroides fragilis, Bacteroides putredinis, Bacteroides thetaiotaomicron, Bacteroides vultagus, Bifidobacterium adolescentis, Bifidobacterium bifidum, Bilophila wadsworthia, Blautia, Butyrivibrio, Campylobacter gracilis, Clostridia cluster III, Clostridia cluster IV, Clostridia cluster IX (Acidaminococcaceae group), Clostridia cluster XI, Clostridia cluster XIII (Peptostreptococcus group), Clostridia cluster XIV, Clostridia cluster XV, Collinsella aerofaciens, Coprococcus, Corynebacterium sunsvallense, Desulfomonas pigra, Dorea formicigenerans, Dorea longicatena, Escherichia coli, Eubacterium hadrum, Eubacterium rectale, Faecalibacteria prausnitzii, Gemella, Lactococcus, Lanchnospira, Mollicutes cluster XVI, Mollicutes cluster XVIII, Prevotella, Rothia mucilaginosa, Ruminococcus callidus, Ruminococcus gnavus, Ruminococcus torques, and Streptococcus.

[40] “Microbiome” broadly refers to the microbes residing on or in body site of a subject or patient. Microbes in a microbiome may include bacteria, viruses, eukaryotic microorganisms, and/or viruses. Individual microbes in a microbiome may be metabolically active, dormant, latent, or exist as spores, may exist planktonically or in biofilms, or may be present in the microbiome in sustainable or transient manner. The microbiome may be a commensal or healthy- state microbiome or a disease-state microbiome. The microbiome may be native to the subject or patient, or components of the microbiome may be modulated, introduced, or depleted due to changes in health state (e.g., precancerous or cancerous state) or treatment conditions (e.g., antibiotic treatment, exposure to different microbes). In some aspects, the microbiome occurs at a mucosal surface. In some aspects, the microbiome is a gut microbiome. In some aspects, the microbiome is a tumor microbiome. [41] A“microbiome profile” or a“microbiome signature” of a tissue or sample refers to an at least partial characterization of the bacterial makeup of a microbiome. In some embodiments, a microbiome profile indicates whether at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more bacterial strains are present or absent in a microbiome. In some embodiments, a microbiome profile indicates whether at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more cancer- associated bacterial strains are present in a sample. In some embodiments, the microbiome profile indicates the relative or absolute amount of each bacterial strain detected in the sample. In some embodiments, the microbiome profile is a cancer-associated microbiome profile. A cancer- associated microbiome profile is a microbiome profile that occurs with greater frequency in a subject who has cancer than in the general population. In some embodiments, the cancer- associated microbiome profile comprises a greater number of or amount of cancer-associated bacteria than is normally present in a microbiome of an otherwise equivalent tissue or sample taken from an individual who does not have cancer.

[42] “Modified” in reference to a bacteria broadly refers to a bacteria that has undergone a change from its wild-type form. Examples of bacterial modifications include genetic

modification, gene expression, phenotype modification, formulation, chemical modification, and dose or concentration. Examples of improved properties are described throughout this specification and include, e.g., attenuation, auxotrophy, homing, or antigenicity. Phenotype modification might include, by way of example, bacteria growth in media that modify the phenotype of a bacterium that increase or decrease virulence.

[43] As used herein, a gene is“overexpressed” in a bacteria if it is expressed at a higher level in an engineered bacteria under at least some conditions than it is expressed by a wild-type bacteria of the same species under the same conditions. Similarly, a gene is“underexpressed” in a bacteria if it is expressed at a lower level in an engineered bacteria under at least some conditions than it is expressed by a wild-type bacteria of the same species under the same conditions.

[44] The terms“polynucleotide”, and“nucleic acid” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three-dimensional structure, and may perform any function. The following are non-limiting examples of polynucleotides: coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), micro RNA (miRNA), silencing RNA (siRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. A polynucleotide may be further modified, such as by conjugation with a labeling component. In all nucleic acid sequences provided herein, U nucleotides are interchangeable with T nucleotides.

[45] An“oncobiome” as used herein comprises pathogenic, tumorigenic and/or cancer- associated microbiota, wherein the microbiota comprises one or more of a virus, a bacterium, a fungus, a protist, a parasite, or another microbe.

[46] “Oncotrophic” or“oncophilic” microbes and bacteria are microbes that are highly associated or present in a cancer microenvironment. They may be preferentially selected for within the environment, preferentially grow in a cancer microenvironment or hone to a said environment.

[47] “Operational taxonomic units” and“OTU(s)” refer to a terminal leaf in a phylogenetic tree and is defined by a nucleic acid sequence, e.g., the entire genome, or a specific genetic sequence, and all sequences that share sequence identity to this nucleic acid sequence at the level of species. In some embodiments the specific genetic sequence may be the 16S sequence or a portion of the 16S sequence. In other embodiments, the entire genomes of two entities are sequenced and compared. In another embodiment, select regions such as multilocus sequence tags (MLST), specific genes, or sets of genes may be genetically compared. For 16S, OTUs that share≥ 97% average nucleotide identity across the entire 16S or some variable region of the 16S are considered the same OTU. See e.g. Claesson MJ, Wang Q, O’Sullivan O, Greene-Diniz R, Cole JR, Ross RP, and O’Toole PW.2010. Comparison of two next-generation sequencing technologies for resolving highly complex microbiota composition using tandem variable 16S rRNA gene regions. Nucleic Acids Res 38: e200. Konstantinidis KT, Ramette A, and Tiedje JM. 2006. The bacterial species definition in the genomic era. Philos Trans R Soc Lond B Biol Sci 361: 1929–1940. For complete genomes, MLSTs, specific genes, other than 16S, or sets of genes OTUs that share≥ 95% average nucleotide identity are considered the same OTU. See e.g., Achtman M, and Wagner M.2008. Microbial diversity and the genetic nature of microbial species. Nat. Rev. Microbiol.6: 431–440. Konstantinidis KT, Ramette A, and Tiedje JM.2006. The bacterial species definition in the genomic era. Philos Trans R Soc Lond B Biol Sci 361: 1929–1940. OTUs are frequently defined by comparing sequences between organisms.

Generally, sequences with less than 95% sequence identity are not considered to form part of the same OTU. OTUs may also be characterized by any combination of nucleotide markers or genes, in particular highly conserved genes (e.g.,“house-keeping” genes), or a combination thereof. Operational Taxonomic Units (OTUs) with taxonomic assignments made to, e.g., genus, species, and phylogenetic clade are provided herein.

[48] As used herein, a substance is“pure” if it is substantially free of other components. The terms“purify,”“purifying” and“purified” refer to bacteria or other material that has been separated from at least some of the components with which it was associated either when initially produced or generated (e.g., whether in nature or in an experimental setting), or during any time after its initial production. Bacteria may be considered purified if it is isolated at or after production, such as from one or more other bacterial components, and a purified microbe or microbial population may contain other materials up to about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or above about 90% and still be considered“purified.” In some embodiments, purified bacteria are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure. Bacteria compositions and the microbial components thereof are, e.g., purified from residual habitat products. In some embodiments the bacteria are concentrated by 2 fold, 3-fold, 4-fold, 5-fold, 10-fold, 100-fold, 1000-fold, 10,000-fold or more than 10,000 fold.

[49] “Residual habitat products” refers to material derived from the habitat for microbiota within or on a subject. For example, microbes live in feces in the gastrointestinal tract, on the skin itself, in saliva, mucus of the respiratory tract, or secretions of the genitourinary tract (i.e., biological matter associated with the microbial community). Substantially free of residual habitat products means that the microbial composition no longer contains the biological matter associated with the microbial environment on or in the human or animal subject and is 100% free, 99% free, 98% free, 97% free, 96% free, or 95% free of any contaminating biological matter associated with the microbial community. Residual habitat products can include abiotic materials (including undigested food) or it can include unwanted microorganisms. Substantially free of residual habitat products may also mean that the microbial composition contains no detectable cells from a human or animal and that only microbial cells are detectable. In one embodiment, substantially free of residual habitat products may also mean that the microbial composition contains no detectable viral (including microbial viruses (e.g., phage)), fungal, mycoplasmal contaminants. In another embodiment, it means that fewer than 1x10 -2 %, 1x10-3%, 1x10 -4 %, 1x10 -5 %, 1x10 -6 %, 1x10 -7 %, 1x10 -8 % of the viable cells in the microbial composition are human or animal, as compared to microbial cells. There are multiple ways to accomplish this degree of purity, none of which are limiting. Thus, contamination may be reduced by isolating desired constituents through multiple steps of streaking to single colonies on solid media until replicate (such as, but not limited to, two) streaks from serial single colonies have shown only a single colony morphology. Alternatively, reduction of contamination can be accomplished by multiple rounds of serial dilutions to single desired cells (e.g., a dilution of 10-8 or 10-9), such as through multiple 10-fold serial dilutions. This can further be confirmed by showing that multiple isolated colonies have similar cell shapes and Gram staining behavior. Other methods for confirming adequate purity include genetic analysis (e.g., PCR, DNA sequencing), serology and antigen analysis, enzymatic and metabolic analysis, and methods using instrumentation such as flow cytometry with reagents that distinguish desired constituents from contaminants.

[50] As used herein,“specific binding” refers to the ability of an antibody to bind to a predetermined antigen or the ability of a polypeptide to bind to its predetermined binding partner. Typically, an antibody or polypeptide specifically binds to its predetermined antigen or binding partner with an affinity corresponding to a K D of about 10 -7 M or less, and binds to the predetermined antigen/binding partner with an affinity (as expressed by K D ) that is at least 10 fold less, at least 100 fold less or at least 1000 fold less than its affinity for binding to a non- specific and unrelated antigen/binding partner (e.g., BSA, casein). Alternatively, specific binding applies more broadly to a two component system where one component is a protein, lipid, or carbohydrate or combination thereof and engages with the second component which is a protein, lipid, carbohydrate or combination thereof in a specific way.

[51] The terms“subject” or“patient” refers to any animal. A subject or a patient described as “in need thereof” refers to one in need of a treatment for a disease. Mammals (i.e., mammalian animals) include humans, laboratory animals (e.g., primates, rats, mice), livestock (e.g., cows, sheep, goats, pigs), and household pets (e.g., dogs, cats, rodents).

[52] “Strain” refers to a member of a bacterial species with a genetic signature such that it may be differentiated from closely-related members of the same bacterial species. The genetic signature may be the absence of all or part of at least one gene, the absence of all or part of at least on regulatory region (e.g., a promoter, a terminator, a riboswitch, a ribosome binding site), the absence (“curing”) of at least one native plasmid, the presence of at least one recombinant gene, the presence of at least one mutated gene, the presence of at least one foreign gene (a gene derived from another species), the presence at least one mutated regulatory region (e.g., a promoter, a terminator, a riboswitch, a ribosome binding site), the presence of at least one non- native plasmid, the presence of at least one antibiotic resistance cassette, or a combination thereof. Genetic signatures between different strains may be identified by PCR amplification optionally followed by DNA sequencing of the genomic region(s) of interest or of the whole genome. In the case in which one strain (compared with another of the same species) has gained or lost antibiotic resistance or gained or lost a biosynthetic capability (such as an auxotrophic strain), strains may be differentiated by selection or counter-selection using an antibiotic or nutrient/metabolite, respectively.

[53] As used herein, the term“treating” a disease in a subject or“treating” a subject having or suspected of having a disease refers to subjecting the subject to a pharmaceutical treatment, e.g., the administration of one or more agents, such that at least one symptom of the disease is decreased or prevented from worsening. Thus, in one embodiment,“treating” refers inter alia to delaying progression, expediting remission, inducing remission, augmenting remission, speeding recovery, increasing efficacy of or decreasing resistance to alternative therapeutics, or a combination thereof. Methods for Identifying Therapeutic Bacteria

[54] In certain aspects, provided herein is a method for identifying bacteria (e.g., bacteria are of a genus, species or strain listed in Table 1, Table 2 and/or Table 3) as being therapeutically effective for the treatment of cancer and/or as being a likely cancer therapeutic. In some embodiments, the bacteria are live bacteria. In some embodiments, the bacteria are attenuated bacteria. In some embodiments, the bacteria are dead bacteria. In some embodiments, the bacteria are engineered bacteria (e.g., bacteria that are modified as disclosed herein).

[55] In certain embodiments, the bacteria are identified based on their ability to induce the expression of a cytokine profile by immune cells (e.g., PBMCs, macrophages, dendritic cells). In certain embodiments, the cytokine profile includes elevated expression of IP-10 (e.g., expression of IP-10 that is at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15- fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90- fold or 100-fold higher than the level expressed by the same type of immune cells cultured in the absence of the bacteria and/or cultured with a control bacteria strain that is not therapeutically effective for the treatment of cancer). In certain embodiments the cytokine profile is an elevated ratio of IP-10 expression to IL-10 expression (e.g., a ratio of IP-10 expression to IL-10 expression that is at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15- fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90- fold or 100-fold higher than the ratio expressed by the same type of immune cells cultured in the absence of the bacteria and/or cultured with a control bacteria strain that is not therapeutically effective for the treatment of cancer). In certain embodiments the cytokine profile is an elevated ratio of IP-10 expression to GM-CSF expression (e.g., a ratio of IP-10 expression to GM-CSF expression that is at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15- fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90- fold or 100-fold higher than the ratio expressed by the same type of immune cells cultured in the absence of the bacteria and/or cultured with a control bacteria strain that is not therapeutically effective for the treatment of cancer).

[56] In certain embodiments, the methods provided herein comprise the steps of: (a) culturing the bacteria with immune cells; and (b) determining the level of IP-10 expression by the immune cells. In certain embodiments, if the level of IP-10 expression by the immune cells is at least 2- fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30- fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold or 100-fold higher than the level of IP-10 expression by the same type of immune cells cultured in the absence of the bacteria, the bacteria are identified as a likely cancer therapeutic. In some embodiments, if the level of IP-10 expression by the immune cells is not at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50- fold, 60-fold, 70-fold, 80-fold, 90-fold or 100-fold higher than the level of IP-10 expression by the same type of immune cells cultured in the absence of the bacteria, the bacteria are identified as not being a likely cancer therapeutic. In certain embodiments, if the level of IP-10 expression by the immune cells is at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10- fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80- fold, 90-fold or 100-fold higher than the level of IP-10 expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer, the bacteria are identified as a likely cancer therapeutic. In some embodiments, if the level of IP-10 expression by the immune cells is not at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold or 100-fold higher than the level of IP-10 expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer, the bacteria are identified as a likely cancer therapeutic.

[57] In certain embodiments, the methods provided herein comprise the steps of: (a) culturing the bacteria with immune cells; and (b) determining the level of IP-10 expression and the level of IL-10 expression by the immune cells. In certain embodiments, if the ratio of IP-10 expression to IL-10 expression by the immune cells is at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8- fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60- fold, 70-fold, 80-fold, 90-fold or 100-fold higher than the ratio of IP-10 expression to IL-10 expression by the same type of immune cells cultured in the absence of the bacteria, the bacteria are identified as a likely cancer therapeutic. In some embodiments, if the ratio of IP-10 expression to IL-10 expression by the immune cells is not at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45- fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold or 100-fold higher than the ratio of IP-10 expression to IL-10 expression by the same type of immune cells cultured in the absence of the bacteria, the bacteria are identified as not being a likely cancer therapeutic. In certain

embodiments, if the ratio of IP-10 expression to IL-10 expression by the immune cells is at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30- fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold or 100-fold higher than the ratio of IP-10 expression to IL-10 expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer, the bacteria are identified as a likely cancer therapeutic. In some embodiments, if the ratio of IP-10 expression to IL-10 expression by the immune cells is not at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold or 100-fold higher than the ratio of IP-10 expression to IL-10 expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer, the bacteria are identified as a likely cancer therapeutic.

[58] In certain embodiments, the methods provided herein comprise the steps of: (a) culturing the bacteria with immune cells; and (b) determining the level of IP-10 expression and the level of GM-CSF expression by the immune cells. In certain embodiments, if the ratio of IP-10 expression to GM-CSF expression by the immune cells is at least 2-fold, 3-fold, 4-fold, 5-fold, 6- fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold or 100-fold higher than the ratio of IP-10 expression to GM-CSF expression by the same type of immune cells cultured in the absence of the bacteria, the bacteria are identified as a likely cancer therapeutic. In some embodiments, if the ratio of IP- 10 expression to GM-CSF expression by the immune cells is not at least 2-fold, 3-fold, 4-fold, 5- fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold or 100-fold higher than the ratio of IP-10 expression to GM-CSF expression by the same type of immune cells cultured in the absence of the bacteria, the bacteria are identified as not being a likely cancer therapeutic. In certain embodiments, if the ratio of IP-10 expression to GM-CSF expression by the immune cells is at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25- fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold or 100-fold higher than the ratio of IP-10 expression to GM-CSF expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer, the bacteria are identified as a likely cancer therapeutic. In some embodiments, if the ratio of IP-10 expression to GM-CSF expression by the immune cells is not at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10- fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80- fold, 90-fold or 100-fold higher than the ratio of IP-10 expression to GM-CSF expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer, the bacteria are identified as a likely cancer therapeutic.

[59] In certain embodiments of the methods provided herein, the immune cells can be any cell capable of expressing IP-10, IL-10 and/or GM-CSF. In certain embodiments, the immune cells are PBMCs. In some embodiments, the immune cells are dendritic cells. In some embodiments, the immune cells are macrophages. In certain embodiments, the immune cells are primary cells. In some embodiments, the immune cells are a cell line. In some embodiments, the immune cells are human cells.

[60] In certain embodiments, the methods provided herein comprise culturing the immune cells with the bacteria. In certain embodiments, the cells are cultured with the bacteria under conditions conducive for expression of IP-10, IL-10 and/or GM-CSF by the immune cells. In certain embodiments, the immune cells are cultured with the bacteria for at least or about 1 minute, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 30 hours, 36 hours, 42 hours or 48 hours.

[61] In certain embodiments, the methods provided herein comprise determining the expression level of a cytokine protein (e.g., IP-10 protein, IL-10 protein, GM-CSF protein). In certain embodiments, any method known in the art for determining cytokine protein levels can be used. For example, in some embodiments the method comprises contacting the sample suspected of containing a the cytokine with a detectably-labeled antibody specific for the cytokine. In certain embodiments, the cytokine levels are determined by ELISA assay or FACS assay. In some embodiments, the cytokine levels are determined using the Human

Cytokine/Chemokine Magnetic Bead Panel (EMD Millipore).

[62] In certain embodiments, the methods comprise determining the expression level of a cytokine mRNA (e.g., IP-10 mRNA, IL-10 mRNA, GM-CSF mRNA). In certain embodiments, any method known in the art for determining cytokine mRNA levels can be used. For example, in some embodiments the method comprises contacting the sample suspected of containing a the cytokine with a detectably-labeled nucleic acid probe specific for the cytokine mRNA. In some embodiments the cytokine mRNA is subjected to an amplification reaction (e.g., a RT-PCR reaction) during the detection process.

[63] In certain embodiments, the methods include the comparison of cytokine expression by the immune cells cultured with the bacteria with the cytokine expression by the same type of immune cells cultured in the absence of the bacteria. In certain embodiments, the methods further comprise culturing the same type and same number of immune cells for the same period of time and under identical conditions but for the absence of the bacteria and determining the resulting expression of one or more cytokines (e.g., IP-10, IL-10 and/or GM-CSF) by the immune cells.

[64] In certain embodiments, the methods include the comparison of cytokine expression by the immune cells cultured with the bacteria with the cytokine expression by the same type of immune cells cultured in the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer, the bacteria are identified as a likely cancer therapeutic. In some embodiments, the control bacteria can be of any bacteria strain that is not therapeutically effective for the treatment of cancer. In some embodiments, the control bacteria can be a therapeutically ineffective strain of a bacterial species listed in Table 1 and/or Table 2. In certain embodiments, the methods further comprise culturing the same type and same number of immune cells for the same period of time and under identical conditions but for the absence of the bacteria but in the presence of a control bacteria strain that is not therapeutically effective for the treatment of cancer, the bacteria are identified as a likely cancer therapeutic and determining the resulting expression of one or more cytokines (e.g., IP-10, IL-10 and/or GM-CSF) by the immune cells. Bacteria

[65] In certain aspects, provided herein are bacteria that are effective cancer therapeutics and/or that are likely cancer therapeutics. In some embodiments, provided herein are bacteria that are identified as effective cancer therapeutics and/or that are likely cancer therapeutics in an method provided herein. In some embodiments, provided herein are bacteria that induce elevated expression of IP-10 in immune cells (e.g., PBMCs, macrophages and/or dendritic cells). In some embodiments, provided herein are bacteria that induce an elevated ratio of IP-10 expression to IL-10 expression in immune cells (e.g., PBMCs, macrophages and/or dendritic cells). In some embodiments, provided herein are bacteria that induce an elevated ratio of IP-10 expression to GM-CSF expression in immune cells (e.g., PBMCs, macrophages and/or dendritic cells).

[66] In certain embodiments, the bacteria provided herein are engineered bacteria. In some embodiments, the bacteria are modified such that they induce elevated expression of IP-10 in immune cells (e.g., PBMCs, macrophages and/or dendritic cells). In some embodiments, the bacteria are modified such that they induce an elevated ratio of IP-10 expression to IL-10 expression in immune cells (e.g., PBMCs, macrophages and/or dendritic cells). In some embodiments, the bacteria are modified such that they induce an elevated ratio of IP-10 expression to GM-CSF expression in immune cells (e.g., PBMCs, macrophages and/or dendritic cells). In some embodiments, the bacteria are modified to enhance oral delivery (e.g., by improving acid resistance, muco-adherence and/or penetration and/or resistance to bile acids, digestive enzymes, resistance to anti-microbial peptides and/or antibody neutralization), to target desired cell types (e.g. M-cells, goblet cells, enterocytes, dendritic cells, macrophages), to enhance their immunomodulatory and/or therapeutic effect of the produced EVs (e.g., either alone or in combination with another therapeutic agent), and/or to enhance immune activation (e.g., through modified production of polysaccharides, pili, fimbriae, adhesins). In some embodiments, the engineered bacteria described herein are modified to improve bacterial manufacturing (e.g., higher oxygen tolerance, stability, improved freeze-thaw tolerance, shorter generation times). For example, in some embodiments, the engineered bacteria described include bacteria harboring one or more genetic changes, such change being an insertion, deletion, translocation, or substitution, or any combination thereof, of one or more nucleotides contained on the bacterial chromosome or endogenous plasmid and/or one or more foreign plasmids, wherein the genetic change may results in the overexpression and/or underexpression of one or more genes. The engineered microbe(s) may be produced using any technique known in the art, including but not limited to site-directed mutagenesis, transposon mutagenesis, knock-outs, knock-ins, polymerase chain reaction mutagenesis, chemical mutagenesis, ultraviolet light mutagenesis, transformation (chemically or by electroporation), phage transduction, directed evolution, or any combination thereof.

[67] As used herein, the term“bacteria” broadly refers to the domain of prokaryotic organisms, including Gram positive and Gram negative organisms. Examples of species and/or strains of bacteria that can be used in the compositions and methods described herein are provided in Tables 1, Table 2, Table 3 and/or elsewhere throughout the specification. In some embodiments, the bacterial strain is a bacterial strain having a genome that has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% 16s, CRISPR or genomic sequence identity to a strain listed in Table 1, Table 2 and/or Table 3. In some embodiments, the bacteria are oncotrophic bacteria. In some embodiments, the bacteria are immunostimulatory bacteria. In certain embodiments, bacteria include a combination of bacterial strains provided herein. In some embodiments, the combination is a combination of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45 or 50 bacterial strains. In some embodiments combination includes bacterial strains listed in Table 1, Table 2 and/or Table 3 and/or bacterial strains having a genome that has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% 16s, CRISPR or genomic sequence identity to a strain listed in Table 1, Table 2 and/or Table 3. Table 1: Exemplary Bacterial Species and Strains

[68] In certain embodiments the bacteria described herein are obligate anaerobic bacteria. Examples of obligate anaerobic bacteria include gram-negative rods (including the genera of Bacteroides, Prevotella, Porphyromonas, Fusobacterium, Bilophila and Sutterella spp.), gram- positive cocci (primarily Peptostreptococcus spp.), gram-positive spore-forming (Clostridium spp.), non-spore-forming bacilli (Actinomyces, Propionibacterium, Eubacterium, Lactobacillus and Bifidobacterium spp.), and gram-negative cocci (mainly Veillonella spp.).

[69] In some embodiments, the bacteria described herein are modified such that they comprise, are linked to, and/or are bound by a therapeutic moiety. In some embodiments, the therapeutic moiety is a cancer-specific moiety. In some embodiments, the cancer-specific moiety has binding specificity for a cancer cell (e.g., has binding specificity for a cancer-specific antigen). In some embodiments, the cancer-specific moiety comprises an antibody or antigen binding fragment thereof. In some embodiments, the cancer-specific moiety comprises a T cell receptor or a chimeric antigen receptor (CAR). In some embodiments, the cancer-specific moiety comprises a ligand for a receptor expressed on the surface of a cancer cell or a receptor-binding fragment thereof. In some embodiments, the cancer-specific moiety is a bipartite fusion protein that has two parts: a first part that binds to and/or is linked to the bacterium and a second part that is capable of binding to a cancer cell (e.g., by having binding specificity for a cancer- specific antigen). In some embodiments, the first part is a fragment of or a full-length peptidoglycan recognition protein, such as PGRP. In some embodiments the first part has binding specificity for the bacteria (e.g., by having binding specificity for a bacterial antigen). In some embodiments, the first and/or second part comprises an antibody or antigen binding fragment thereof. In some embodiments, the first and/or second part comprises a T cell receptor or a chimeric antigen receptor (CAR). In some embodiments, the first and/or second part comprises a ligand for a receptor expressed on the surface of a cancer cell or a receptor-binding fragment thereof. In certain embodiments, co-administration of the cancer-specific moiety with the bacteria (either in combination or in separate administrations) increases the targeting of the bacteria to the cancer cells.

[70] In some embodiments, the bacteria described herein is modified such that they comprise, are linked to, and/or are bound by a magnetic and/or paramagnetic moiety (e.g., a magnetic bead). In some embodiments, the magnetic and/or paramagnetic moiety is comprised by and/or directly linked to the bacteria. In some embodiments, the magnetic and/or paramagnetic moiety is linked to and/or a part of an bacteria-binding moiety that that binds to the bacteria. In some embodiments, the bacteria-binding moiety is a fragment of or a full-length peptidoglycan recognition protein, such as PGRP. In some embodiments the bacteria-binding moiety has binding specificity for the bacteria (e.g., by having binding specificity for a bacterial antigen). In some embodiments, the bacteria-binding moiety comprises an antibody or antigen binding fragment thereof. In some embodiments, the bacteria-binding moiety comprises a T cell receptor or a chimeric antigen receptor (CAR). In some embodiments, the bacteria-binding moiety comprises a ligand for a receptor expressed on the surface of a cancer cell or a receptor-binding fragment thereof. In certain embodiments, co-administration of the magnetic and/or

paramagnetic moiety with the bacteria (either together or in separate administrations) can be used to increase the targeting of the bacteria to cancer calls and/or a part of a subject where cancer cells are present. Pharmaceutical Compositions

[71] In certain embodiments, the methods provided herein are pharmaceutical compositions comprising bacteria provided herein (e.g., a bacterial composition). In some embodiments, the bacterial composition comprises bacteria described herein and a pharmaceutically acceptable carrier.

[72] In certain aspects, provided are pharmaceutical compositions for administration subjects. In some embodiments, the pharmaceutical compositions are combined with additional active and/or inactive materials in order to produce a final product, which may be in single dosage unit or in a multi-dose format.

[73] In some embodiments the composition comprises at least one carbohydrate. A

“carbohydrate” refers to a sugar or polymer of sugars. The terms“saccharide,”“polysaccharide,” “carbohydrate,” and“oligosaccharide” may be used interchangeably. Most carbohydrates are aldehydes or ketones with many hydroxyl groups, usually one on each carbon atom of the molecule. Carbohydrates generally have the molecular formula C n H 2n O n . A carbohydrate may be a monosaccharide, a disaccharide, trisaccharide, oligosaccharide, or polysaccharide. The most basic carbohydrate is a monosaccharide, such as glucose, sucrose, galactose, mannose, ribose, arabinose, xylose, and fructose. Disaccharides are two joined monosaccharides. Exemplary disaccharides include sucrose, maltose, cellobiose, and lactose. Typically, an oligosaccharide includes between three and six monosaccharide units (e.g., raffinose, stachyose), and

polysaccharides include six or more monosaccharide units. Exemplary polysaccharides include starch, glycogen, and cellulose. Carbohydrates may contain modified saccharide units such as 2’- deoxyribose wherein a hydroxyl group is removed, 2’-fluororibose wherein a hydroxyl group is replaced with a fluorine, or N-acetylglucosamine, a nitrogen-containing form of glucose (e.g., 2’- fluororibose, deoxyribose, and hexose). Carbohydrates may exist in many different forms, for example, conformers, cyclic forms, acyclic forms, stereoisomers, tautomers, anomers, and isomers.

[74] In some embodiments the composition comprises at least one lipid. As used herein a “lipid” includes fats, oils, triglycerides, cholesterol, phospholipids, fatty acids in any form including free fatty acids. Fats, oils and fatty acids can be saturated, unsaturated (cis or trans) or partially unsaturated (cis or trans). In some embodiments the lipid comprises at least one fatty acid selected from lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16:1), margaric acid (17:0), heptadecenoic acid (17:1), stearic acid (18:0), oleic acid (18:1), linoleic acid (18:2), linolenic acid (18:3), octadecatetraenoic acid (18:4), arachidic acid (20:0), eicosenoic acid (20:1), eicosadienoic acid (20:2), eicosatetraenoic acid (20:4), eicosapentaenoic acid (20:5) (EPA), docosanoic acid (22:0), docosenoic acid (22:1), docosapentaenoic acid (22:5), docosahexaenoic acid (22:6) (DHA), and tetracosanoic acid (24:0). In some embodiments the composition comprises at least one modified lipid, for example a lipid that has been modified by cooking. [75] In some embodiments the composition comprises at least one supplemental mineral or mineral source. Examples of minerals include, without limitation: chloride, sodium, calcium, iron, chromium, copper, iodine, zinc, magnesium, manganese, molybdenum, phosphorus, potassium, and selenium. Suitable forms of any of the foregoing minerals include soluble mineral salts, slightly soluble mineral salts, insoluble mineral salts, chelated minerals, mineral complexes, non-reactive minerals such as carbonyl minerals, and reduced minerals, and combinations thereof.

[76] In some embodiments the composition comprises at least one supplemental vitamin. The at least one vitamin can be fat-soluble or water soluble vitamins. Suitable vitamins include but are not limited to vitamin C, vitamin A, vitamin E, vitamin B12, vitamin K, riboflavin, niacin, vitamin D, vitamin B6, folic acid, pyridoxine, thiamine, pantothenic acid, and biotin. Suitable forms of any of the foregoing are salts of the vitamin, derivatives of the vitamin, compounds having the same or similar activity of the vitamin, and metabolites of the vitamin.

[77] In some embodiments the composition comprises an excipient. Non-limiting examples of suitable excipients include a buffering agent, a preservative, a stabilizer, a binder, a compaction agent, a lubricant, a dispersion enhancer, a disintegration agent, a flavoring agent, a sweetener, and a coloring agent.

[78] In some embodiments the excipient is a buffering agent. Non-limiting examples of suitable buffering agents include sodium citrate, magnesium carbonate, magnesium bicarbonate, calcium carbonate, and calcium bicarbonate.

[79] In some embodiments the excipient comprises a preservative. Non-limiting examples of suitable preservatives include antioxidants, such as alpha-tocopherol and ascorbate, and antimicrobials, such as parabens, chlorobutanol, and phenol.

[80] In some embodiments the composition comprises a binder as an excipient. Non-limiting examples of suitable binders include starches, pregelatinized starches, gelatin,

polyvinylpyrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fatty acid alcohol, polyethylene glycol, polyols, saccharides, oligosaccharides, and combinations thereof.

[81] In some embodiments the composition comprises a lubricant as an excipient. Non- limiting examples of suitable lubricants include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene monostearate, talc, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil.

[82] In some embodiments the composition comprises a dispersion enhancer as an excipient. Non-limiting examples of suitable dispersants include starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high HLB emulsifier surfactants.

[83] In some embodiments the composition comprises a disintegrant as an excipient. In some embodiments the disintegrant is a non-effervescent disintegrant. Non-limiting examples of suitable non-effervescent disintegrants include starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro- crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, and tragacanth. In some embodiments the disintegrant is an effervescent disintegrant. Non-limiting examples of suitable effervescent disintegrants include sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid.

[84] In some embodiments, the composition is a food product (e.g., a food or beverage) such as a health food or beverage, a food or beverage for infants, a food or beverage for pregnant women, athletes, senior citizens or other specified group, a functional food, a beverage, a food or beverage for specified health use, a dietary supplement, a food or beverage for patients, or an animal feed. Specific examples of the foods and beverages include various beverages such as juices, refreshing beverages, tea beverages, drink preparations, jelly beverages, and functional beverages; alcoholic beverages such as beers; carbohydrate-containing foods such as rice food products, noodles, breads, and pastas; paste products such as fish hams, sausages, paste products of seafood; retort pouch products such as curries, food dressed with a thick starchy sauces, and Chinese soups; soups; dairy products such as milk, dairy beverages, ice creams, cheeses, and yogurts; fermented products such as fermented soybean pastes, yogurts, fermented beverages, and pickles; bean products; various confectionery products, including biscuits, cookies, and the like, candies, chewing gums, gummies, cold desserts including jellies, cream caramels, and frozen desserts; instant foods such as instant soups and instant soy-bean soups; microwavable foods; and the like. Further, the examples also include health foods and beverages prepared in the forms of powders, granules, tablets, capsules, liquids, pastes, and jellies. [85] In some embodiments the composition is a food product for animals, including humans. The animals, other than humans, are not particularly limited, and the composition can be used for various livestock, poultry, pets, experimental animals, and the like. Specific examples of the animals include pigs, cattle, horses, sheep, goats, chickens, wild ducks, ostriches, domestic ducks, dogs, cats, rabbits, hamsters, mice, rats, monkeys, and the like, but the animals are not limited thereto. Cancer Therapeutics

[86] In certain aspects, the methods provided herein include the administration to a subject of a pharmaceutical composition described herein either alone or in combination with an additional therapeutic. In some embodiments, the additional therapeutic is a cancer therapeutic.

[87] In some embodiments the bacteria are administered to the subject before the therapeutic is administered (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours before or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days before). In some embodiments the bacteria are administered to the subject after the therapeutic is administered (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours after or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days after). In some embodiments, the bacteria and the therapeutic are administered to the subject simultaneously or nearly simultaneously (e.g., administrations occur within an hour of each other). In some embodiments, the subject is administered an antibiotic before the bacteria are administered to the subject (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours before or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days before). In some embodiments, the subject is administered an antibiotic after the bacteria are administered to the subject (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours before or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days after). In some embodiments, the bacteria and the antibiotic are administered to the subject simultaneously or nearly simultaneously (e.g., administrations occur within an hour of each other). [88] In some embodiments, the additional therapeutic is a cancer therapeutic. In some embodiments, the cancer therapeutic is a chemotherapeutic agent. Examples of such

chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide,

triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin;

callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine,

cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammalI and calicheamicin omegal1; dynemicin, including dynemicin A;

bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomysins, actinomycin, authrarnycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino- doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5- FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate,

epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin;

losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK polysaccharide complex); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''- trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol;

pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel and doxetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine;

methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above.

[89] In some embodiments, the cancer therapeutic is a cancer immunotherapy agent.

Immunotherapy refers to a treatment that uses a subject’s immune system to treat cancer, e.g., checkpoint inhibitors, cancer vaccines, cytokines, cell therapy, CAR-T cells, and dendritic cell therapy. Non-limiting examples of immunotherapies are checkpoint inhibitors include

Nivolumab (BMS, anti-PD-1), Pembrolizumab (Merck, anti-PD-1), Ipilimumab (BMS, anti- CTLA-4), MEDI4736 (AstraZeneca, anti-PD-L1), and MPDL3280A (Roche, anti-PD-L1). Other immunotherapies may be tumor vaccines, such as Gardail, Cervarix, BCG, sipulencel-T, Gp100:209-217, AGS-003, DCVax-L, Algenpantucel-L, Tergenpantucel-L, TG4010, ProstAtak, Prostvac-V/R-TRICOM, Rindopepimul, E75 peptide acetate, IMA901, POL-103A,

Belagenpumatucel-L, GSK1572932A, MDX-1279, GV1001, and Tecemotide. Immunotherapy may be administered via injection (e.g., intravenously, intratumorally, subcutaneously, or into lymph nodes), but may also be administered orally, topically, or via aerosol. Immunotherapies may comprise adjuvants such as cytokines. [90] In some embodiments, the immunotherapy agent is an immune checkpoint inhibitor. Immune checkpoint inhibition broadly refers to inhibiting the checkpoints that cancer cells can produce to prevent or downregulate an immune response. Examples of immune checkpoint proteins include, but are not limited to, CTLA4, PD-1, PD-L1, PD-L2, A2AR, B7-H3, B7-H4, BTLA, KIR, LAG3, TIM-3 or VISTA. Immune checkpoint inhibitors can be antibodies or antigen binding fragments thereof that bind to and inhibit an immune checkpoint protein.

Examples of immune checkpoint inhibitors include, but are not limited to, nivolumab, pembrolizumab, pidilizumab, AMP-224, AMP-514, STI-A1110, TSR-042, RG-7446, BMS- 936559, MEDI-4736, MSB-0020718C, AUR-012 and STI-A1010.

[91] In some embodiments, the immunotherapy agent is an antibody or antigen binding fragment thereof that, for example, binds to a cancer-associated antigen. Examples of cancer- associated antigens include, but are not limited to, adipophilin, AIM-2, ALDH1A1, alpha- actinin-4, alpha-fetoprotein (“AFP”), ARTC1, B-RAF, BAGE-1, BCLX (L), BCR-ABL fusion protein b3a2, beta-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen (“CEA”), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin D1, Cyclin-A1, dek-can fusion protein, DKK1, EFTUD2, Elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen (“ETA”), ETV6-AML1 fusion protein, EZH2, FGF5, FLT3-ITD, FN1, G250/MN/CAIX, GAGE-1,2,8, GAGE-3,4,5,6,7, GAS7, glypican-3, GnTV, gp100/Pmel17, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL, HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDO1, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kallikrein 4, KIF20A, KK-LC-1, KKLC1, KM-HN-1, KMHN1 also known as CCDC110, LAGE-1, LDLR-fucosyltransferaseAS fusion protein, Lengsin, M-CSF, MAGE-A1, MAGE-A10, MAGE-A12, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm-2, ME1, Melan-A/MART-1, Meloe, Midkine, MMP-2, MMP-7, MUC1, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88-A, neo-PAP, NFYC, NY-BR-1, NY-ESO-1/LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml-RARalpha fusion protein, polymorphic epithelial mucin (“PEM”), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB38/NY-MEL-1, RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, secernin 1, SIRT2, SNRPD1, SOX10, Sp17, SPA17, SSX-2, SSX-4, STEAP1, survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Triosephosphate isomerase, TRP-1/gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase (“TYR”), VEGF, WT1, XAGE-1b/GAGED2a. In some embodiments, the antigen is a neo-antigen.

[92] In some embodiments, the immunotherapy agent is a cancer vaccine and/or a component of a cancer vaccine (e.g., an antigenic peptide and/or protein). The cancer vaccine can be a protein vaccine, a nucleic acid vaccine or a combination thereof. For example, in some embodiments, the cancer vaccine comprises a polypeptide comprising an epitope of a cancer- associated antigen. In some embodiments, the cancer vaccine comprises a nucleic acid (e.g., DNA or RNA, such as mRNA) that encodes an epitope of a cancer-associated antigen. Examples of cancer-associated antigens include, but are not limited to, adipophilin, AIM-2, ALDH1A1, alpha-actinin-4, alpha-fetoprotein (“AFP”), ARTC1, B-RAF, BAGE-1, BCLX (L), BCR-ABL fusion protein b3a2, beta-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen (“CEA”), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin D1, Cyclin-A1, dek-can fusion protein, DKK1, EFTUD2, Elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen (“ETA”), ETV6-AML1 fusion protein, EZH2, FGF5, FLT3-ITD, FN1,

G250/MN/CAIX, GAGE-1,2,8, GAGE-3,4,5,6,7, GAS7, glypican-3, GnTV, gp100/Pmel17, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL, HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDO1, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kallikrein 4, KIF20A, KK-LC-1, KKLC1, KM-HN-1, KMHN1 also known as CCDC110, LAGE-1, LDLR- fucosyltransferaseAS fusion protein, Lengsin, M-CSF, MAGE-A1, MAGE-A10, MAGE-A12, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm-2, ME1, Melan-A/MART-1, Meloe, Midkine, MMP-2, MMP-7, MUC1, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88-A, neo-PAP, NFYC, NY-BR-1, NY-ESO-1/LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml-RARalpha fusion protein, polymorphic epithelial mucin (“PEM”), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB38/NY-MEL-1, RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, secernin 1, SIRT2, SNRPD1, SOX10, Sp17, SPA17, SSX-2, SSX-4, STEAP1, survivin, SYT-SSX1 or - SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3,

Triosephosphate isomerase, TRP-1/gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase (“TYR”), VEGF, WT1, XAGE-1b/GAGED2a. In some embodiments, the antigen is a neo-antigen. In some embodiments, the cancer vaccine is administered with an adjuvant. Examples of adjuvants include, but are not limited to, an immune modulatory protein, Adjuvant 65, α-GalCer, aluminum phosphate, aluminum hydroxide, calcium phosphate, β-Glucan Peptide, CpG ODN DNA, GPI-0100, lipid A, lipopolysaccharide, Lipovant, Montanide, N-acetyl-muramyl-L-alanyl- D-isoglutamine, Pam3CSK4, quil A , cholera toxin (CT) and heat-labile toxin from

enterotoxigenic Escherichia coli (LT) including derivatives of these (CTB, mmCT, CTA1-DD, LTB, LTK63, LTR72, dmLT) and trehalose dimycolate.

[93] In some embodiments, the immunotherapy agent is an immune modulating protein to the subject. In some embodiments, the immune modulatory protein is a cytokine or chemokine. Examples of immune modulating proteins include, but are not limited to, B lymphocyte chemoattractant ("BLC"), C-C motif chemokine 11 ("Eotaxin-1"), Eosinophil chemotactic protein 2 ("Eotaxin-2"), Granulocyte colony-stimulating factor ("G-CSF"), Granulocyte macrophage colony-stimulating factor ("GM-CSF"), 1-309, Intercellular Adhesion Molecule 1 ("ICAM-1"), Interferon alpha (“IFN-alpha”), Interferon beta (“IFN-beta”) Interferon gamma ("IFN-gamma"), Interlukin-1 alpha ("IL-1 alpha"), Interlukin-1 beta ("IL-1 beta"), Interleukin 1 receptor antagonist ("IL-1 ra"), Interleukin-2 ("IL-2"), Interleukin-4 ("IL-4"), Interleukin-5 ("IL- 5"), Interleukin-6 ("IL-6"), Interleukin-6 soluble receptor ("IL-6 sR"), Interleukin-7 ("IL-7"), Interleukin-8 ("IL-8"), Interleukin- 10 ("IL-10"), Interleukin- 11 ("IL-11"), Subunit beta of Interleukin- 12 ("IL-12 p40" or "IL-12 p70"), Interleukin-13 ("IL-13"), Interleukin-15 ("IL-15"), Interleukin-16 ("IL-16"), Interleukin-17A-F ("IL-17A-F"), Interleukin-18 ("IL-18"), Interleukin- 21 ("IL-21"), Interleukin-22 ("IL-22"), Interleukin-23 ("IL-23"), Interleukin-33 ("IL-33"), Chemokine (C-C motif) Ligand 2 ("MCP-1"), Macrophage colony-stimulating factor ("M-CSF"), Monokine induced by gamma interferon ("MIG"), Chemokine (C-C motif) ligand 2 ("MIP-1 alpha"), Chemokine (C-C motif) ligand 4 ("MIP-1 beta"), Macrophage inflammatory protein- 1 - delta ("MIP-1 delta"), Platelet-derived growth factor subunit B ("PDGF-BB"), Chemokine (C-C motif) ligand 5, Regulated on Activation, Normal T cell Expressed and Secreted ("RANTES"), TIMP metallopeptidase inhibitor 1 ("TIMP-1"), TIMP metallopeptidase inhibitor 2 ("TIMP-2"), Tumor necrosis factor, lymphotoxin-alpha ("TNF alpha"), Tumor necrosis factor, lymphotoxin- beta ("TNF beta"), Soluble TNF receptor type 1 ("sTNFRI"), sTNFRIIAR, Brain-derived neurotrophic factor ("BDNF"), Basic fibroblast growth factor ("bFGF"), Bone morphogenetic protein 4 ("BMP-4"), Bone morphogenetic protein 5 ("BMP-5"), Bone morphogenetic protein 7 ("BMP-7"), Nerve growth factor ("b-NGF"), Epidermal growth factor ("EGF"), Epidermal growth factor receptor ("EGFR"), Endocrine-gland-derived vascular endothelial growth factor ("EG-VEGF"), Fibroblast growth factor 4 ("FGF-4"), Keratinocyte growth factor ("FGF-7"), Growth differentiation factor 15 ("GDF-15"), Glial cell-derived neurotrophic factor ("GDNF"), Growth Hormone, Heparin-binding EGF-like growth factor ("HB-EGF"), Hepatocyte growth factor ("HGF"), Insulin-like growth factor binding protein 1 ("IGFBP-1"), Insulin-like growth factor binding protein 2 ("IGFBP-2"), Insulin-like growth factor binding protein 3 (" IGFBP-3"), Insulin-like growth factor binding protein 4 ("IGFBP-4"), Insulin-like growth factor binding protein 6 ("IGFBP-6"), Insulin-like growth factor 1 ("IGF-1"), Insulin, Macrophage colony- stimulating factor ("M-CSF R"), Nerve growth factor receptor ("NGF R"), Neurotrophin-3 ("NT- 3"), Neurotrophin-4 ("NT-4"), Osteoclastogenesis inhibitory factor ("Osteoprotegerin"), Platelet- derived growth factor receptors ("PDGF-AA"), Phosphatidylinositol-glycan biosynthesis ("PIGF"), Skp, Cullin, F-box containing comples ("SCF"), Stem cell factor receptor ("SCF R"), Transforming growth factor alpha ("TGFalpha"), Transforming growth factor beta-1 ("TGF beta 1"), Transforming growth factor beta-3 ("TGF beta 3"), Vascular endothelial growth factor ("VEGF"), Vascular endothelial growth factor receptor 2 ("VEGFR2"), Vascular endothelial growth factor receptor 3 ("VEGFR3"), VEGF-D 6Ckine, Tyrosine-protein kinase receptor UFO ("Axl"), Betacellulin ("BTC"), Mucosae-associated epithelial chemokine ("CCL28"), Chemokine (C-C motif) ligand 27 ("CTACK"), Chemokine (C-X-C motif) ligand 16 ("CXCL16"), C-X-C motif chemokine 5 ("ENA-78"), Chemokine (C-C motif) ligand 26 ("Eotaxin-3"), Granulocyte chemotactic protein 2 ("GCP-2"), GRO, Chemokine (C-C motif) ligand 14 ("HCC-l"),

Chemokine (C-C motif) ligand 16 ("HCC-4"), Interleukin-9 ("IL-9"), Interleukin-17 F ("IL- 17F"), Interleukin- 18-binding protein ("IL-18 BPa"), Interleukin-28 A ("IL-28A"), Interleukin 29 ("IL-29"), Interleukin 31 ("IL-31"), C-X-C motif chemokine 10 ("IP-10"), Chemokine receptor CXCR3 ("I-TAC"), Leukemia inhibitory factor ("LIF"), Light, Chemokine (C motif) ligand ("Lymphotactin"), Monocyte chemoattractant protein 2 ("MCP-2"), Monocyte chemoattractant protein 3 ("MCP-3"), Monocyte chemoattractant protein 4 ("MCP-4"),

Macrophage-derived chemokine ("MDC"), Macrophage migration inhibitory factor ("MIF"), Chemokine (C-C motif) ligand 20 ("MIP-3 alpha"), C-C motif chemokine 19 ("MIP-3 beta"), Chemokine (C-C motif) ligand 23 ("MPIF-1"), Macrophage stimulating protein alpha chain ("MSPalpha"), Nucleosome assembly protein 1-like 4 ("NAP-2"), Secreted phosphoprotein 1 ("Osteopontin"), Pulmonary and activation-regulated cytokine ("PARC"), Platelet factor 4 ("PF4"), Stroma cell-derived factor- 1 alpha ("SDF-1 alpha"), Chemokine (C-C motif) ligand 17 ("TARC"), Thymus-expressed chemokine ("TECK"), Thymic stromal lymphopoietin ("TSLP 4- IBB"), CD 166 antigen ("ALCAM"), Cluster of Differentiation 80 ("B7-1"), Tumor necrosis factor receptor superfamily member 17 ("BCMA"), Cluster of Differentiation 14 ("CD14"), Cluster of Differentiation 30 ("CD30"), Cluster of Differentiation 40 ("CD40 Ligand"),

Carcinoembryonic antigen-related cell adhesion molecule 1 (biliary glycoprotein) ("CEACAM- 1"), Death Receptor 6 ("DR6"), Deoxythymidine kinase ("Dtk"), Type 1 membrane glycoprotein ("Endoglin"), Receptor tyrosine-protein kinase erbB-3 ("ErbB3"), Endothelial-leukocyte adhesion molecule 1 ("E-Selectin"), Apoptosis antigen 1 ("Fas"), Fms-like tyrosine kinase 3 ("Flt-3L"), Tumor necrosis factor receptor superfamily member 1 ("GITR"), Tumor necrosis factor receptor superfamily member 14 ("HVEM"), Intercellular adhesion molecule 3 ("ICAM- 3"), IL-1 R4, IL-1 RI, IL-10 Rbeta, IL-17R, IL-2Rgamma, IL-21R, Lysosome membrane protein 2 ("LIMPII"), Neutrophil gelatinase-associated lipocalin ("Lipocalin-2"), CD62L ("L-Selectin"), Lymphatic endothelium ("LYVE-1"), MHC class I polypeptide-related sequence A ("MICA"), MHC class I polypeptide-related sequence B ("MICB"), NRGl-betal, Beta-type platelet-derived growth factor receptor ("PDGF Rbeta"), Platelet endothelial cell adhesion molecule ("PECAM- 1"), RAGE, Hepatitis A virus cellular receptor 1 ("TIM-1"), Tumor necrosis factor receptor superfamily member IOC ("TRAIL R3"), Trappin protein transglutaminase binding domain ("Trappin-2"), Urokinase receptor ("uPAR"), Vascular cell adhesion protein 1 ("VCAM-1"), XEDARActivin A, Agouti-related protein ("AgRP"), Ribonuclease 5 ("Angiogenin"),

Angiopoietin 1, Angiostatin, Catheprin S, CD40, Cryptic family protein IB ("Cripto-1"), DAN, Dickkopf-related protein 1 ("DKK-1"), E-Cadherin, Epithelial cell adhesion molecule

("EpCAM"), Fas Ligand (FasL or CD95L), Fcg RIIB/C, FoUistatin, Galectin-7, Intercellular adhesion molecule 2 ("ICAM-2"), IL-13 Rl, IL-13R2, IL-17B, IL-2 Ra, IL-2 Rb, IL-23, LAP, Neuronal cell adhesion molecule ("NrCAM"), Plasminogen activator inhibitor- 1 ("PAI-1"), Platelet derived growth factor receptors ("PDGF-AB"), Resistin, stromal cell-derived factor 1 ("SDF-1 beta"), sgpl30, Secreted frizzled-related protein 2 ("ShhN"), Sialic acid-binding immunoglobulin-type lectins ("Siglec-5"), ST2, Transforming growth factor-beta 2 ("TGF beta 2"), Tie-2, Thrombopoietin ("TPO"), Tumor necrosis factor receptor superfamily member 10D ("TRAIL R4"), Triggering receptor expressed on myeloid cells 1 ("TREM-1"), Vascular endothelial growth factor C ("VEGF-C"), VEGFRlAdiponectin, Adipsin ("AND"), Alpha- fetoprotein ("AFP"), Angiopoietin-like 4 ("ANGPTL4"), Beta-2-microglobulin ("B2M"), Basal cell adhesion molecule ("BCAM"), Carbohydrate antigen 125 ("CA125"), Cancer Antigen 15-3 ("CA15-3"), Carcinoembryonic antigen ("CEA"), cAMP receptor protein ("CRP"), Human Epidermal Growth Factor Receptor 2 ("ErbB2"), Follistatin, Follicle-stimulating hormone ("FSH"), Chemokine (C-X-C motif) ligand 1 ("GRO alpha"), human chorionic gonadotropin ("beta HCG"), Insulin-like growth factor 1 receptor ("IGF-1 sR"), IL-1 sRII, IL-3, IL-18 Rb, IL- 21, Leptin, Matrix metalloproteinase-1 ("MMP-1"), Matrix metalloproteinase-2 ("MMP-2"), Matrix metalloproteinase-3 ("MMP-3"), Matrix metalloproteinase-8 ("MMP-8"), Matrix metalloproteinase-9 ("MMP-9"), Matrix metalloproteinase-10 ("MMP-10"), Matrix

metalloproteinase-13 ("MMP-13"), Neural Cell Adhesion Molecule ("NCAM-1"), Entactin ("Nidogen-1"), Neuron specific enolase ("NSE"), Oncostatin M ("OSM"), Procalcitonin, Prolactin, Prostate specific antigen ("PSA"), Sialic acid-binding Ig-like lectin 9 ("Siglec-9"), ADAM 17 endopeptidase ("TACE"), Thyroglobulin, Metalloproteinase inhibitor 4 ("TIMP-4"), TSH2B4, Disintegrin and metalloproteinase domain-containing protein 9 ("ADAM-9"), Angiopoietin 2, Tumor necrosis factor ligand superfamily member 13/ Acidic leucine-rich nuclear phosphoprotein 32 family member B ("APRIL"), Bone morphogenetic protein 2 ("BMP- 2"), Bone morphogenetic protein 9 ("BMP-9"), Complement component 5a ("C5a"), Cathepsin L, CD200, CD97, Chemerin, Tumor necrosis factor receptor superfamily member 6B ("DcR3"), Fatty acid-binding protein 2 ("FABP2"), Fibroblast activation protein, alpha ("FAP"), Fibroblast growth factor 19 ("FGF-19"), Galectin-3, Hepatocyte growth factor receptor ("HGF R"), IFN- gammalpha/beta R2, Insulin-like growth factor 2 ("IGF-2"), Insulin-like growth factor 2 receptor ("IGF-2 R"), Interleukin-1 receptor 6 ("IL-1R6"), Interleukin 24 ("IL-24"), Interleukin 33 ("IL- 33", Kallikrein 14, Asparaginyl endopeptidase ("Legumain"), Oxidized low-density lipoprotein receptor 1 ("LOX-1"), Mannose-binding lectin ("MBL"), Neprilysin ("NEP"), Notch homolog 1, translocation-associated (Drosophila) ("Notch-1"), Nephroblastoma overexpressed ("NOV"), Osteoactivin, Programmed cell death protein 1 ("PD-1"), N-acetylmuramoyl-L-alanine amidase ("PGRP-5"), Serpin A4, Secreted frizzled related protein 3 ("sFRP-3"), Thrombomodulin, Tolllike receptor 2 ("TLR2"), Tumor necrosis factor receptor superfamily member 10A ("TRAIL Rl"), Transferrin ("TRF"), WIF-lACE-2, Albumin, AMICA, Angiopoietin 4, B-cell activating factor ("BAFF"), Carbohydrate antigen 19-9 ("CA19-9"), CD 163 , Clusterin, CRT AM, Chemokine (C-X-C motif) ligand 14 ("CXCL14"), Cystatin C, Decorin ("DCN"), Dickkopf- related protein 3 ("Dkk-3"), Delta-like protein 1 ("DLL1"), Fetuin A, Heparin-binding growth factor 1 ("aFGF"), Folate receptor alpha ("FOLR1"), Furin, GPCR-associated sorting protein 1 ("GASP-1"), GPCR-associated sorting protein 2 ("GASP-2"), Granulocyte colony-stimulating factor receptor ("GCSF R"), Serine protease hepsin ("HAI-2"), Interleukin-17B Receptor ("IL- 17B R"), Interleukin 27 ("IL-27"), Lymphocyte-activation gene 3 ("LAG-3"), Apolipoprotein A- V ("LDL R"), Pepsinogen I, Retinol binding protein 4 ("RBP4"), SOST, Heparan sulfate proteoglycan ("Syndecan-1"), Tumor necrosis factor receptor superfamily member 13B

("TACI"), Tissue factor pathway inhibitor ("TFPI"), TSP-1, Tumor necrosis factor receptor superfamily, member 10b ("TRAIL R2"), TRANCE, Troponin I, Urokinase Plasminogen Activator ("uPA"), Cadherin 5, type 2 or VE-cadherin (vascular endothelial) also known as CD144 ("VE-Cadherin"), WNTl-inducible-signaling pathway protein 1 ("WISP-1"), and Receptor Activator of Nuclear Factor κ B ("RANK").

[94] In some embodiments, the cancer therapeutic agent is an anti-cancer compound.

Exemplary anti-cancer compounds include, but are not limited to, Alemtuzumab (Campath®), Alitretinoin (Panretin®), Anastrozole (Arimidex®), Bevacizumab (Avastin®), Bexarotene (Targretin®), Bortezomib (Velcade®), Bosutinib (Bosulif®), Brentuximab vedotin (Adcetris®), Cabozantinib (Cometriq™), Carfilzomib (Kyprolis™), Cetuximab (Erbitux®), Crizotinib (Xalkori®), Dasatinib (Sprycel®), Denileukin diftitox (Ontak®), Erlotinib hydrochloride (Tarceva®), Everolimus (Afinitor®), Exemestane (Aromasin®), Fulvestrant (Faslodex®), Gefitinib (Iressa®), Ibritumomab tiuxetan (Zevalin®), Imatinib mesylate (Gleevec®),

Ipilimumab (Yervoy™), Lapatinib ditosylate (Tykerb®), Letrozole (Femara®), Nilotinib (Tasigna®), Ofatumumab (Arzerra®), Panitumumab (Vectibix®), Pazopanib hydrochloride (Votrient®), Pertuzumab (Perjeta™), Pralatrexate (Folotyn®), Regorafenib (Stivarga®), Rituximab (Rituxan®), Romidepsin (Istodax®), Sorafenib tosylate (Nexavar®), Sunitinib malate (Sutent®), Tamoxifen, Temsirolimus (Torisel®), Toremifene (Fareston®), Tositumomab and 131I-tositumomab (Bexxar®), Trastuzumab (Herceptin®), Tretinoin (Vesanoid®), Vandetanib (Caprelsa®), Vemurafenib (Zelboraf®), Vorinostat (Zolinza®), and Ziv-aflibercept (Zaltrap®).

[95] Exemplary anti-cancer compounds that modify the function of proteins that regulate gene expression and other cellular functions (e.g., HDAC inhibitors, retinoid receptor ligants) are Vorinostat (Zolinza®), Bexarotene (Targretin®) and Romidepsin (Istodax®), Alitretinoin (Panretin®), and Tretinoin (Vesanoid®).

[96] Exemplary anti-cancer compounds that induce apoptosis (e.g., proteasome inhibitors, antifolates) are Bortezomib (Velcade®), Carfilzomib (Kyprolis™), and Pralatrexate (Folotyn®).

[97] Exemplary anti-cancer compounds that increase anti-tumor immune response (e.g., anti CD20, anti CD52; anti-cytotoxic T-lymphocyte-associated antigen-4) are Rituximab (Rituxan®), Alemtuzumab (Campath®), Ofatumumab (Arzerra®), and Ipilimumab (Yervoy™).

[98] Exemplary anti-cancer compounds that deliver toxic agents to cancer cells (e.g., anti- CD20-radionuclide fusions; IL-2-diphtheria toxin fusions; anti-CD30- monomethylauristatin E (MMAE)-fusions) are Tositumomab and 131I-tositumomab (Bexxar®)and Ibritumomab tiuxetan (Zevalin®), Denileukin diftitox (Ontak®), and Brentuximab vedotin (Adcetris®).

[99] Other exemplary anti-cancer compounds are small molecule inhibitors and conjugates thereof of, e.g., Janus kinase, ALK, Bcl-2, PARP, PI3K, VEGF receptor, Braf, MEK, CDK, and HSP90.

[100] Exemplary platinum-based anti-cancer compounds include, for example, cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, Nedaplatin, Triplatin, and Lipoplatin. Other metal-based drugs suitable for treatment include, but are not limited to ruthenium-based compounds, ferrocene derivatives, titanium-based compounds, and gallium-based compounds.

[101] In some embodiments, the cancer therapeutic is a radioactive moiety that comprises a radionuclide. Exemplary radionuclides include, but are not limited to Cr-51, Cs-131, Ce-134, Se-75, Ru-97, I-125, Eu-149, Os-189m, Sb-119, I-123, Ho-161, Sb-117, Ce-139, In-111, Rh-103m, Ga-67, Tl-201, Pd-103, Au-195, Hg-197, Sr-87m, Pt-191, P-33, Er-169, Ru-103, Yb- 169, Au-199, Sn-121, Tm-167, Yb-175, In-113m, Sn-113, Lu-177, Rh-105, Sn-117m, Cu-67, Sc- 47, Pt-195m, Ce-141, I-131, Tb-161, As-77, Pt-197, Sm-153, Gd-159, Tm-173, Pr-143, Au-198, Tm-170, Re-186, Ag-111, Pd-109, Ga-73, Dy-165, Pm-149, Sn-123, Sr-89, Ho-166, P-32, Re- 188, Pr-142, Ir-194, In-114m/In-114, and Y-90.

[102] In some embodiments, the cancer therapeutic is an antibiotic. For example, if the presence of a cancer-associated bacteria and/or a cancer-associated microbiome profile is detected according to the methods provided herein, antibiotics can be administered to eliminate the cancer-associated bacteria from the subject.“Antibiotics” broadly refers to compounds capable of inhibiting or preventing a bacterial infection. Antibiotics can be classified in a number of ways, including their use for specific infections, their mechanism of action, their bioavailability, or their spectrum of target microbe (e.g., Gram-negative vs. Gram-positive bacteria, aerobic vs. anaerobic bacteria, etc.) and these may be used to kill specific bacteria in specific areas of the host (“niches”) (Leekha, et al 2011. General Principles of Antimicrobial Therapy. Mayo Clin Proc.86(2): 156-167). In certain embodiments, antibiotics can be used to selectively target bacteria of a specific niche. In some embodiments, antibiotics known to treat a particular infection that includes a cancer niche may be used to target cancer-associated microbes, including cancer-associated bacteria in that niche. In other embodiments, antibiotics are administered after the bacterial treatment. In some embodiments, antibiotics are administered after the bacterial treatment to remove the engraftment.

[103] In some aspects, antibiotics can be selected based on their bactericidal or bacteriostatic properties. Bactericidal antibiotics include mechanisms of action that disrupt the cell wall (e.g., β-lactams), the cell membrane (e.g., daptomycin), or bacterial DNA (e.g., fluoroquinolones). Bacteriostatic agents inhibit bacterial replication and include sulfonamides, tetracyclines, and macrolides, and act by inhibiting protein synthesis. Furthermore, while some drugs can be bactericidal in certain organisms and bacteriostatic in others, knowing the target organism allows one skilled in the art to select an antibiotic with the appropriate properties. In certain treatment conditions, bacteriostatic antibiotics inhibit the activity of bactericidal antibiotics. Thus, in certain embodiments, bactericidal and bacteriostatic antibiotics are not combined.

[104] Antibiotics include, but are not limited to aminoglycosides, ansamycins, carbacephems, carbapenems, cephalosporins, glycopeptides, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, oxazolidonones, penicillins, polypeptide antibiotics, quinolones, fluoroquinolone, sulfonamides, tetracyclines, and anti-mycobacterial compounds, and combinations thereof.

[105] Aminoglycosides include, but are not limited to Amikacin, Gentamicin,

Kanamycin, Neomycin, Netilmicin, Tobramycin, Paromomycin, and Spectinomycin.

Aminoglycosides are effective, e.g., against Gram-negative bacteria, such as Escherichia coli, Klebsiella, Pseudomonas aeruginosa, and Francisella tularensis, and against certain aerobic bacteria but less effective against obligate/facultative anaerobes. Aminoglycosides are believed to bind to the bacterial 30S or 50S ribosomal subunit thereby inhibiting bacterial protein synthesis.

[106] Ansamycins include, but are not limited to, Geldanamycin, Herbimycin, Rifamycin, and Streptovaricin. Geldanamycin and Herbimycin are believed to inhibit or alter the function of Heat Shock Protein 90.

[107] Carbacephems include, but are not limited to, Loracarbef. Carbacephems are believed to inhibit bacterial cell wall synthesis.

[108] Carbapenems include, but are not limited to, Ertapenem, Doripenem,

Imipenem/Cilastatin, and Meropenem. Carbapenems are bactericidal for both Gram-positive and Gram-negative bacteria as broad-spectrum antibiotics. Carbapenems are believed to inhibit bacterial cell wall synthesis.

[109] Cephalosporins include, but are not limited to, Cefadroxil, Cefazolin, Cefalotin, Cefalothin, Cefalexin, Cefaclor, Cefamandole, Cefoxitin, Cefprozil, Cefuroxime, Cefixime, Cefdinir, Cefditoren, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefepime, Ceftaroline fosamil,and Ceftobiprole. Selected

Cephalosporins are effective, e.g., against Gram-negative bacteria and against Gram-positive bacteria, including Pseudomonas, certain Cephalosporins are effective against methicillin- resistant Staphylococcus aureus (MRSA). Cephalosporins are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.

[110] Glycopeptides include, but are not limited to, Teicoplanin, Vancomycin, and Telavancin. Glycopeptides are effective, e.g., against aerobic and anaerobic Gram-positive bacteria including MRSA and Clostridium difficile. Glycopeptides are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.

[111] Lincosamides include, but are not limited to, Clindamycin and Lincomycin. Lincosamides are effective, e.g., against anaerobic bacteria, as well as Staphylococcus, and Streptococcus. Lincosamides are believed to bind to the bacterial 50S ribosomal subunit thereby inhibiting bacterial protein synthesis.

[112] Lipopeptides include, but are not limited to, Daptomycin. Lipopeptides are effective, e.g., against Gram-positive bacteria. Lipopeptides are believed to bind to the bacterial membrane and cause rapid depolarization. [113] Macrolides include, but are not limited to, Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin, Telithromycin, and Spiramycin. Macrolides are effective, e.g., against Streptococcus and Mycoplasma. Macrolides are believed to bind to the bacterial or 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis.

[114] Monobactams include, but are not limited to, Aztreonam. Monobactams are effective, e.g., against Gram-negative bacteria. Monobactams are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.

[115] Nitrofurans include, but are not limited to, Furazolidone and Nitrofurantoin.

[116] Oxazolidonones include, but are not limited to, Linezolid, Posizolid, Radezolid, and Torezolid. Oxazolidonones are believed to be protein synthesis inhibitors.

[117] Penicillins include, but are not limited to, Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Mezlocillin, Methicillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Temocillin and Ticarcillin. Penicillins are effective, e.g., against Gram-positive bacteria, facultative anaerobes, e.g., Streptococcus, Borrelia, and Treponema. Penicillins are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.

[118] Penicillin combinations include, but are not limited to, Amoxicillin/clavulanate, Ampicillin/sulbactam, Piperacillin/tazobactam, and Ticarcillin/clavulanate.

[119] Polypeptide antibiotics include, but are not limited to, Bacitracin, Colistin, and Polymyxin B and E. Polypeptide Antibiotics are effective, e.g., against Gram-negative bacteria. Certain polypeptide antibiotics are believed to inhibit isoprenyl pyrophosphate involved in synthesis of the peptidoglycan layer of bacterial cell walls, while others destabilize the bacterial outer membrane by displacing bacterial counter-ions.

[120] Quinolones and Fluoroquinolone include, but are not limited to, Ciprofloxacin, Enoxacin, Gatifloxacin, Gemifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Trovafloxacin, Grepafloxacin, Sparfloxacin, and Temafloxacin. Quinolones/Fluoroquinolone are effective, e.g., against Streptococcus and Neisseria.

Quinolones/Fluoroquinolone are believed to inhibit the bacterial DNA gyrase or topoisomerase IV, thereby inhibiting DNA replication and transcription.

[121] Sulfonamides include, but are not limited to, Mafenide, Sulfacetamide,

Sulfadiazine, Silver sulfadiazine, Sulfadimethoxine, Sulfamethizole, Sulfamethoxazole, Sulfanilimide, Sulfasalazine, Sulfisoxazole, Trimethoprim-Sulfamethoxazole (Co-trimoxazole), and Sulfonamidochrysoidine. Sulfonamides are believed to inhibit folate synthesis by competitive inhibition of dihydropteroate synthetase, thereby inhibiting nucleic acid synthesis.

[122] Tetracyclines include, but are not limited to, Demeclocycline, Doxycycline, Minocycline, Oxytetracycline, and Tetracycline. Tetracyclines are effective, e.g., against Gram- negative bacteria. Tetracyclines are believed to bind to the bacterial 30S ribosomal subunit thereby inhibiting bacterial protein synthesis.

[123] Anti-mycobacterial compounds include, but are not limited to, Clofazimine, Dapsone, Capreomycin, Cycloserine, Ethambutol, Ethionamide, Isoniazid, Pyrazinamide, Rifampicin, Rifabutin, Rifapentine, and Streptomycin.

[124] Suitable antibiotics also include arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, platensimycin, quinupristin/dalfopristin, tigecycline, tinidazole, trimethoprim amoxicillin/clavulanate, ampicillin/sulbactam, amphomycin ristocetin, azithromycin, bacitracin, buforin II, carbomycin, cecropin Pl, clarithromycin, erythromycins, furazolidone, fusidic acid, Na fusidate, gramicidin, imipenem, indolicidin, josamycin, magainan II, metronidazole, nitroimidazoles, mikamycin, mutacin B-Ny266, mutacin B-JHl 140, mutacin J-T8, nisin, nisin A, novobiocin, oleandomycin, ostreogrycin, piperacillin/tazobactam, pristinamycin, ramoplanin, ranalexin, reuterin, rifaximin, rosamicin, rosaramicin, spectinomycin, spiramycin, staphylomycin, streptogramin, streptogramin A, synergistin, taurolidine, teicoplanin, telithromycin, ticarcillin/clavulanic acid, triacetyloleandomycin, tylosin, tyrocidin, tyrothricin, vancomycin, vemamycin, and virginiamycin. Administration

[125] In certain aspects, provided herein is a method of delivering a pharmaceutical composition described herein to a subject. In some embodiments of the methods provided herein, the pharmaceutical composition is administered in conjunction with the administration of an additional therapeutic. In some embodiments, the pharmaceutical composition comprises bacteria co-formulated with the additional therapeutic. In some embodiments, the pharmaceutical composition is co-administered with the additional therapeutic. In some embodiments, the additional therapeutic is administered to the subject before administration of the pharmaceutical composition (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 minutes before, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 hours before, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days before). In some embodiments, the additional therapeutic is administered to the subject after administration of the

pharmaceutical composition (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 minutes after, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 hours after, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days after). In some embodiments the same mode of delivery are used to deliver both the pharmaceutical composition and the additional therapeutic. In some embodiments different modes of delivery are used to administer the pharmaceutical composition and the additional therapeutic. For example, in some embodiments the pharmaceutical composition is administered orally while the additional therapeutic is administered via injection (e.g., an intravenous, intramuscular and/or intratumoral injection).

[126] In certain embodiments, the pharmaceutical compositions, dosage forms, and kits described herein can be administered in conjunction with any other conventional anti-cancer treatment, such as, for example, radiation therapy and surgical resection of the tumor. These treatments may be applied as necessary and/or as indicated and may occur before, concurrent with or after administration of the pharmaceutical compositions, dosage forms, and kits described herein.

[127] The dosage regimen can be any of a variety of methods and amounts, and can be determined by one skilled in the art according to known clinical factors. As is known in the medical arts, dosages for any one patient can depend on many factors, including the subject's species, size, body surface area, age, sex, immunocompetence, and general health, the particular microorganism to be administered, duration and route of administration, the kind and stage of the disease, for example, tumor size, and other compounds such as drugs being administered concurrently. In addition to the above factors, such levels can be affected by the infectivity of the microorganism, and the nature of the microorganism, as can be determined by one skilled in the art. In the present methods, appropriate minimum dosage levels of microorganisms can be levels sufficient for the microorganism to survive, grow and replicate. The dose of the pharmaceutical compositions described herein may be appropriately set or adjusted in accordance with the dosage form, the route of administration, the degree or stage of a target disease, and the like. For example, the general effective dose of the agents may range between 0.01 mg/kg body weight/day and 1000 mg/kg body weight/day, between 0.1 mg/kg body weight/day and 1000 mg/kg body weight/day, 0.5 mg/kg body weight/day and 500 mg/kg body weight/day, 1 mg/kg body weight/day and 100 mg/kg body weight/day, or between 5 mg/kg body weight/day and 50 mg/kg body weight/day. The effective dose may be 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 500, or 1000 mg/kg body weight/day or more, but the dose is not limited thereto.

[128] In some embodiments, the dose administered to a subject is sufficient to prevent disease (e.g., autoimmune disease, inflammatory disease, metabolic disease, cancer), delay its onset, or slow or stop its progression. One skilled in the art will recognize that dosage will depend upon a variety of factors including the strength of the particular compound employed, as well as the age, species, condition, and body weight of the subject. The size of the dose will also be determined by the route, timing, and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular compound and the desired physiological effect.

[129] Suitable doses and dosage regimens can be determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. An effective dosage and treatment protocol can be determined by routine and conventional means, starting e.g., with a low dose in laboratory animals and then increasing the dosage while monitoring the effects, and systematically varying the dosage regimen as well. Animal studies are commonly used to determine the maximal tolerable dose ("MTD") of bioactive agent per kilogram weight. Those skilled in the art regularly extrapolate doses for efficacy, while avoiding toxicity, in other species, including humans.

[130] In accordance with the above, in therapeutic applications, the dosages of the active agents used in accordance with the invention vary depending on the active agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage.

Generally, the dose should be sufficient to result in slowing, and preferably regressing, the growth of the tumors and most preferably causing complete regression of the cancer. [131] Separate administrations can include any number of two or more administrations, including two, three, four, five or six administrations. One skilled in the art can readily determine the number of administrations to perform or the desirability of performing one or more additional administrations according to methods known in the art for monitoring therapeutic methods and other monitoring methods provided herein. Accordingly, the methods provided herein include methods of providing to the subject one or more administrations of an pharmaceutical composition, where the number of administrations can be determined by monitoring the subject, and, based on the results of the monitoring, determining whether or not to provide one or more additional administrations. Deciding on whether or not to provide one or more additional administrations can be based on a variety of monitoring results.

[132] The time period between administrations can be any of a variety of time periods. The time period between administrations can be a function of any of a variety of factors, including monitoring steps, as described in relation to the number of administrations, the time period for a subject to mount an immune response and/or the time period for a subject to clear the bacteria from normal tissue. In one example, the time period can be a function of the time period for a subject to mount an immune response; for example, the time period can be more than the time period for a subject to mount an immune response, such as more than about one week, more than about ten days, more than about two weeks, or more than about a month; in another example, the time period can be less than the time period for a subject to mount an immune response, such as less than about one week, less than about ten days, less than about two weeks, or less than about a month. In another example, the time period can be a function of the time period for a subject to clear the bacteria from normal tissue; for example, the time period can be more than the time period for a subject to clear the bacteria from normal tissue, such as more than about a day, more than about two days, more than about three days, more than about five days, or more than about a week.

[133] In some embodiments, the delivery of an additional therapeutic in combination with the pharmaceutical composition described herein reduces the adverse effects and/or improves the efficacy of the additional therapeutic.

[134] The effective dose of an additional therapeutic described herein is the amount of the therapeutic agent that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, with the least toxicity to the patient. The effective dosage level can be identified using the methods described herein and will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions administered, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. In general, an effective dose of an additional therapy will be the amount of the therapeutic agent which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[135] The toxicity of an additional therapy is the level of adverse effects experienced by the subject during and following treatment. Adverse events associated with additional therapy toxicity include, but are not limited to, abdominal pain, acid indigestion, acid reflux, allergic reactions, alopecia, anaphylasix, anemia, anxiety, lack of appetite, arthralgias, asthenia, ataxia, azotemia, loss of balance, bone pain, bleeding, blood clots, low blood pressure, elevated blood pressure, difficulty breathing, bronchitis, bruising, low white blood cell count, low red blood cell count, low platelet count, cardiotoxicity, cystitis, hemorrhagic cystitis, arrhythmias, heart valve disease, cardiomyopathy, coronary artery disease, cataracts, central neurotoxicity, cognitive impairment, confusion, conjunctivitis, constipation, coughing, cramping, cystitis, deep vein thrombosis, dehydration, depression, diarrhea, dizziness, dry mouth, dry skin, dyspepsia, dyspnea, edema, electrolyte imbalance, esophagitis, fatigue, loss of fertility, fever, flatulence, flushing, gastric reflux, gastroesophageal reflux disease, genital pain, granulocytopenia, gynecomastia, glaucoma, hair loss, hand-foot syndrome, headache, hearing loss, heart failure, heart palpitations, heartburn, hematoma, hemorrhagic cystitis, hepatotoxicity, hyperamylasemia, hypercalcemia, hyperchloremia, hyperglycemia, hyperkalemia, hyperlipasemia,

hypermagnesemia, hypernatremia, hyperphosphatemia, hyperpigmentation,

hypertriglyceridemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypochloremia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, impotence, infection, injection site reactions, insomnia, iron deficiency, itching, joint pain, kidney failure, leukopenia, liver dysfunction, memory loss, menopause, mouth sores, mucositis, muscle pain, myalgias, myelosuppression, myocarditis, neutropenic fever, nausea, nephrotoxicity, neutropenia, nosebleeds, numbness, ototoxicity, pain, palmar-plantar erythrodysesthesia, pancytopenia, pericarditis, peripheral neuropathy, pharyngitis, photophobia, photosensitivity, pneumonia, pneumonitis, proteinuria, pulmonary embolus, pulmonary fibrosis, pulmonary toxicity, rash, rapid heart beat, rectal bleeding, restlessness, rhinitis, seizures, shortness of breath, sinusitis, thrombocytopenia, tinnitus, urinary tract infection, vaginal bleeding, vaginal dryness, vertigo, water retention, weakness, weight loss, weight gain, and xerostomia. In general, toxicity is acceptable if the benefits to the subject achieved through the therapy outweigh the adverse events experienced by the subject due to the therapy. Cancer

[136] In some embodiments, the methods and compositions described herein relate to the treatment of cancer. In some embodiments, any cancer can be treated using the methods described herein. Examples of cancers that may treated by methods and compositions described herein include, but are not limited to, cancer cells from the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, or uterus. In addition, the cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular

adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp;

adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant;

branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma;

acidophil carcinoma; oxyphilic adenocarcinoma; basophil carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma; nonencapsulating sclerosing carcinoma; adrenal cortical carcinoma; endometroid carcinoma; skin appendage carcinoma; apocrine adenocarcinoma; sebaceous adenocarcinoma; ceruminous adenocarcinoma; mucoepidermoid carcinoma; cystadenocarcinoma; papillary

cystadenocarcinoma; papillary serous cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma; infiltrating duct carcinoma; medullary carcinoma; lobular carcinoma; inflammatory carcinoma; paget's disease, mammary; acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma w/squamous metaplasia; thymoma, malignant; ovarian stromal tumor, malignant; thecoma, malignant; granulosa cell tumor, malignant; and roblastoma, malignant; sertoli cell carcinoma; leydig cell tumor, malignant; lipid cell tumor, malignant; paraganglioma, malignant; extra-mammary paraganglioma, malignant; pheochromocytoma; glomangiosarcoma; malignant melanoma; amelanotic melanoma;

superficial spreading melanoma; malig melanoma in giant pigmented nevus; epithelioid cell melanoma; blue nevus, malignant; sarcoma; fibrosarcoma; fibrous histiocytoma, malignant; myxosarcoma; liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal

rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; mixed tumor, malignant; mullerian mixed tumor; nephroblastoma; hepatoblastoma; carcinosarcoma; mesenchymoma, malignant; brenner tumor, malignant; phyllodes tumor, malignant; synovial sarcoma;

mesothelioma, malignant; dysgerminoma; embryonal carcinoma; teratoma, malignant; struma ovarii, malignant; choriocarcinoma; mesonephroma, malignant; hemangiosarcoma;

hemangioendothelioma, malignant; kaposi's sarcoma; hemangiopericytoma, malignant;

lymphangiosarcoma; osteosarcoma; juxtacortical osteosarcoma; chondrosarcoma;

chondroblastoma, malignant; mesenchymal chondrosarcoma; giant cell tumor of bone; ewing's sarcoma; odontogenic tumor, malignant; ameloblastic odontosarcoma; ameloblastoma, malignant; ameloblastic fibrosarcoma; pinealoma, malignant; chordoma; glioma, malignant; ependymoma; astrocytoma; protoplasmic astrocytoma; fibrillary astrocytoma; astroblastoma; glioblastoma; oligodendroglioma; oligodendroblastoma; primitive neuroectodermal; cerebellar sarcoma; ganglioneuroblastoma; neuroblastoma; retinoblastoma; olfactory neurogenic tumor; meningioma, malignant; neurofibrosarcoma; neurilemmoma, malignant; granular cell tumor, malignant; malignant lymphoma; Hodgkin's disease; Hodgkin's lymphoma; paragranuloma; malignant lymphoma, small lymphocytic; malignant lymphoma, large cell, diffuse; malignant lymphoma, follicular; mycosis fungoides; other specified non-Hodgkin's lymphomas; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphoid leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and hairy cell leukemia. [137] In some embodiments, the methods and compositions provided herein relate to the treatment of a leukemia. The term "leukemia" is meant broadly progressive, malignant diseases of the hematopoietic organs/systems and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Non-limiting examples of leukemia diseases include, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, undifferentiated cell leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, plasmacytic leukemia, and promyelocytic leukemia.

[138] In some embodiments, the methods and compositions provided herein relate to the treatment of a carcinoma. The term "carcinoma" refers to a malignant growth made up of epithelial cells tending to infiltrate the surrounding tissues, and/or resist physiological and non- physiological cell death signals and gives rise to metastases. Non-limiting exemplary types of carcinomas include, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma,

basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma,

bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiennoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniform carcinoma, gelatinous carcinoma, giant cell carcinoma, signet- ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, carcinoma villosum, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, naspharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, and carcinoma scroti.

[139] In some embodiments, the methods and compositions provided herein relate to the treatment of a sarcoma. The term "sarcoma" generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar, heterogeneous, or homogeneous substance. Sarcomas include, but are not limited to, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, endometrial sarcoma, stromal sarcoma, Ewing' s sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma. [140] Additional exemplary neoplasias that can be treated using the methods and compositions described herein include Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, small-cell lung tumors, primary brain tumors, stomach cancer, colon cancer, malignant pancreatic insulanoma, malignant carcinoid, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, cervical cancer, endometrial cancer, and adrenal cortical cancer.

[141] In some embodiments, the cancer treated is a melanoma. The term "melanoma" is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Non- limiting examples of melanomas are Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, nodular melanoma subungal melanoma, and superficial spreading melanoma.

[142] Particular categories of tumors that can be treated using methods and

compositions described herein include lymphoproliferative disorders, breast cancer, ovarian cancer, prostate cancer, cervical cancer, endometrial cancer, bone cancer, liver cancer, stomach cancer, colon cancer, pancreatic cancer, cancer of the thyroid, head and neck cancer, cancer of the central nervous system, cancer of the peripheral nervous system, skin cancer, kidney cancer, as well as metastases of all the above. Particular types of tumors include hepatocellular carcinoma, hepatoma, hepatoblastoma, rhabdomyosarcoma, esophageal carcinoma, thyroid carcinoma, ganglioblastoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, Ewing's tumor,

leimyosarcoma, rhabdotheliosarcoma, invasive ductal carcinoma, papillary adenocarcinoma, melanoma, pulmonary squamous cell carcinoma, basal cell carcinoma, adenocarcinoma (well differentiated, moderately differentiated, poorly differentiated or undifferentiated),

bronchioloalveolar carcinoma, renal cell carcinoma, hypernephroma, hypernephroid

adenocarcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, testicular tumor, lung carcinoma including small cell, non-small and large cell lung carcinoma, bladder carcinoma, glioma, astrocyoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, retinoblastoma, neuroblastoma, colon carcinoma, rectal carcinoma, hematopoietic malignancies including all types of leukemia and lymphoma including: acute myelogenous leukemia, acute myelocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, mast cell leukemia, multiple myeloma, myeloid lymphoma, Hodgkin' s lymphoma, non-Hodgkin' s lymphoma, plasmacytoma, colorectal cancer, rectal cancer, Merkel Cell carcinoma, and salivary gland carcinoma.

[143] Cancers treated in certain embodiments also include precancerous lesions, e.g., actinic keratosis (solar keratosis), moles (dysplastic nevi), acitinic chelitis (farmer's lip), cutaneous horns, Barrett's esophagus, atrophic gastritis, dyskeratosis congenita, sideropenic dysphagia, lichen planus, oral submucous fibrosis, actinic (solar) elastosis and cervical dysplasia.

[144] Cancers treated in some embodiments include non-cancerous or benign tumors, e.g., of endodermal, ectodermal or mesenchymal origin, including, but not limited to

cholangioma, colonic polyp, adenoma, papilloma, cystadenoma, liver cell adenoma,

hydatidiform mole, renal tubular adenoma, squamous cell papilloma, gastric polyp, hemangioma, osteoma, chondroma, lipoma, fibroma, lymphangioma, leiomyoma, rhabdomyoma, astrocytoma, nevus, meningioma, and ganglioneuroma. Methods of Making Engineered Bacteria

[145] In certain aspects, provided herein are methods of making engineered bacteria (e.g., bacteria engineered to induce IP-10 expression by immune cells, bacteria engineered to induce an elevated ratio of IP-10 expression to IL-10 expression by immune cells, bacteria engineered to induce an elevated ratio of IP-10 expression to GM-CSF expression by immune cells). In some embodiments, the engineered bacteria are modified to enhance certain desirable properties. In some embodiments, the engineered bacteria are modified to have enhanced oral delivery (e.g., by improving acid resistance and/or resistance to bile acids), to enhance the immunomodulatory and/or therapeutic effect (e.g., either alone or in combination with another therapeutic agent), to enhance immune activation and/or to improve bacterial manufacturing (e.g., higher oxygen tolerance, improved freeze-thaw tolerance, shorter generation times). The engineered bacteria may be produced using any technique known in the art, including but not limited to site-directed mutagenesis, transposon mutagenesis, knock-outs, knock-ins, polymerase chain reaction mutagenesis, chemical mutagenesis, ultraviolet light mutagenesis, transformation (chemically or by electroporation), phage transduction, directed evolution, CRISPR/Cas9, or any combination thereof.

[146] In some embodiments of the methods provided herein, the bacterium is modified by directed evolution. In some embodiments, the directed evolution comprises exposure of the bacterium to an environmental condition and selection of bacterium with improved survival and/or growth under the environmental condition. In some embodiments, the method comprises a screen of mutagenized bacteria using an assay that identifies enhanced bacterium. In some embodiments, the method further comprises mutagenizing the bacteria (e.g., by exposure to chemical mutagens and/or UV radiation) followed by an assay to detect bacteria having the desired phenotype (e.g., an in vivo assay, an ex vivo assay, or an in vitro assay).

[147] In some embodiments, the bacterium provided herein are modified by exposure to a stress-inducing environment (e.g., an environment that induces envelope stress). For example, in some embodiments, the bacterium is grown in the presence of subinhibitory concentrations of an antibiotic described herein (e.g., 0.1-1 µg/mL chloramphenicol, or 0.1-0.3 µg/mL

gentamicin). In some embodiments, host antimicrobial peptides (e.g., lysozyme, defensins, and Reg proteins) are used in place of or in combination with antibiotics. In some embodiments, bacterially-produced antimicrobial peptides (e.g., bacteriocins and microcins) are used. In some embodiments, the stress is temperature stress (e.g., growth at 37-50°C). In some embodiments, the stress is carbon limitation stress (e.g., growth in a media comprising limited carbon sources, such as media with carbon source restricted below 1% (w/v)). In some embodiments, the stress is salt stress (e.g., growth in a medium containing 0.5M NaCl). In some embodiments, the stress is UV stress (e.g., growth under a UV lamp, either throughout the entire cultivation period or only during a portion of the cultivation period). In some embodiments, the stress is reactive oxygen stress (e.g., growth in media containing subinhibitory concentrations of hydrogen peroxide, such as 250-1,000 µM hydrogen peroxide). In some embodiments, a combination of the stresses disclosed herein are applied to the bacterium. EXAMPLES

Example 1: Testing Bacteria for Induction of Cytokine Expression by Human Macrophages Materials [148] Reagents utilized in the assay are listed in Table 4. Specific solutions utilized during in the assay are listed in Table 5. Special equipment used in the assay are listed in Table 6.

Table 4: Assay Reagents

Table 5: Assay Solutions

Table 6: Assay Equipment Buffy Coat Processing Protocol to Obtain PBMCs

[149] Fresh, unpurified healthy donor human buffy coats (n=3) were obtained from Research Blood Components, LLC. PBMCs were isolated by Ficoll Paque gradient

centrifugation by standard procedures. Specifically, 15mL of Ficoll-Paque PLUS (GE

Healthcare) was layered beneath 35mL of buffy coat diluted 1:1 to 1:4 in PBS or RPMI in a 50mL conical. The 50mL conicals were centrifuged at 400g for 50 minutes with the acceleration and deceleration speed set to 3. The PBMC interface layer was carefully collected with a glass Pasteur pipette and washed with RPMI at least 2 times to remove residual Ficoll. Red blood cells were lysed with RBC lysis buffer (Qiagen) for 5 minutes on ice. The cells were quenched with complete immune cell medium. Platelets were removed by centrifugation at 200g for 15 minutes. PBMCs were re-suspended in MACS Miltenyi rinsing solution and counted with viability dye to obtain total viable cell count for each donor PBMC preparation. Purification and Preparation of CD11b+ Cells from PBMCs

[150] A MACS Miltenyi standard protocol was carried out to purify CD11b+ cells from the human PBMCs according to manufactures instructions. Cells were thoroughly washed, suspended in appropriate buffer, kept cold, and processed quickly for best results. Per kit protocol, CD11b+ cells were positively selected for using anti-CD11b specific magnetic separation technology. The cells were resuspended in 90 μL of buffer per 107 total cells.10 μL of CD11b Microbeads was added per 107 total cells. The cell suspension was mixed thoroughly and incubated for 15 minutes at 4C in the dark. The cells were thoroughly washed by adding 1−2 mL of buffer per 107 cells and centrifuged at 300×g for 10 minutes. The supernatant was removed completely. The cells were resuspended at 108 cells in 500 μL of buffer for magnetic separation.
The cell suspension was applied to pre-rinsed magnetic column. Unlabeled cells were allowed to pass through the column and were discarded. The column was washed with an appropriate amount of buffer per manufacturer’s instructions. An appropriate amount of buffer was added to the column, column was removed from magnetic, and buffer was flushed through with a plunger. Flushed (CD11b+ labeled) cells were collected, washed, and counted prior to in vitro culture. In Vitro Human Cell-microbe Co-culture with CD11b+ Cells

[151] The purified CD11b+ cells were washed twice in complete RPMI immune cell media (without antibiotics) to remove residual EDTA from Miltenyi separation buffer. The CD11b+ cells were counted with viability dye and re-suspended at 2,000,000 cells per ml (200,000 cells per 100ul).200,000 CD11b+ cells per well (100ul) were plated in 96-well tissue culture-treated plates using a multichannel pipette. The cells could adhere to the plates in the 37C incubator overnight. The following morning, non-adherent cells were gently removed from the plates, leaving strongly-adherent CD11b+ (macrophage/myeloid) cells, and thus replacing fresh non-antibiotic containing complete cell media in the process. Human cell plates for the three donors were loaded into an anaerobic chamber for automated loading of pre-quantified anaerobic bacteria into co-culture with the mammalian cells via Beckman Coulter technology. 100,000 microbes per well were incubated with CD11b+ cells. For positive controls, cells from each donor were also treated with LPS (100ng/ml) + IFNg (100 ng/ml) to induce the

M1(Classical) phenotype, or with IL-4 (10ug/ml) + IL-13 (10ug/ml) to induce an M2

(alternative) phenotype. A TLR agonist control panel was also included. Within the anaerobic chamber, microbe-cell co-culture plates were loaded into a small anaerobic box and flushed with 1% O2. Plate-containing boxes were incubated in the 37C incubator for 24hr. After 24hr, plates were removed from the incubator. Supernatants were collected and stored at 80C until cytokine analysis was carried out. Cytokine analysis of Human CD11b+ Cell– Microbe Co-culture Supernatants

[152] The standard Luminex MagPix protocol (EMD Millipore) for cytokine analysis was carried out according to manufacturer’s instructions to assess cytokines in supernatant (IL-6, IL-10, TNFa, IL-1b, MCP1, VEGF, CXCL10, IL-12p40). Cytokines assessed are listed in Table 7. Table 7: Human Cytokines Assessed

[153] As seen in Figure 1, Blautia strain A (ATCC Deposit Number PTA-125134) and Bifidobacterium animalis ssp. lactis Strain A (ATCC Deposit Number PTA-125097) induced significantly higher levels of IP-10 and higher ratios of IP-10 to IL-10 compared to three control bacteria strains that are not therapeutically effective for the treatment of cancer. Control Strain A is a therapeutically ineffective Bifidobacterium bifidum strain. Control Strain B is a

therapeutically ineffective Bifidobacterium sp. strain. Control Strain C is also a therapeutically ineffective Bifidobacterium bifidum strain. Example 2: Testing Bacteria for Induction of Cytokine Expression by Human PBMCs

Buffy Coat Processing Protocol to Obtain PBMCs

[154] Fresh, unpurified healthy donor human buffy coats (n=3) were obtained from Research Blood Components, LLC. PBMCs were isolated by Ficoll Paque gradient

centrifugation by standard procedures. Specifically, 15mL of Ficoll-Paque PLUS (GE

Healthcare) was layered beneath 35mL of buffy coat diluted 1:1 to 1:4 in PBS or RPMI in a 50mL conical. The 50mL conicals were centrifuged at 400g for 50 minutes with the acceleration and deceleration speed set to 3. The PBMC interface layer was carefully collected with a glass Pasteur pipette and washed with RPMI at least 2 times to remove residual Ficoll. Red blood cells were lysed with RBC lysis buffer (Qiagen) for 5 minutes on ice. The cells were quenched with complete immune cell medium. Platelets were removed by centrifugation at 200g for 15 minutes. PBMCs were re-suspended in RPMI media. In Vitro Human Cell-microbe Co-culture with PBMCs

[155] The purified PBMCs were washed twice in complete RPMI immune cell media (without antibiotics). The PBMCs were counted with viability dye and re-suspended at 1,000,000 cells per ml (100,000 cells per 100ul).100,000 PBMCs per well (100ul) were plated in 96-well tissue culture-treated plates using a multichannel pipette. The cells were allowed to adhere to the plates in a 37C incubator overnight. The following morning, human cell plates for the three donors were loaded into an anaerobic chamber for automated loading of pre-quantified anaerobic bacteria into co-culture with the mammalian cells via Beckman Coulter technology.100,000 microbes per well were incubated with PBMCs. For positive controls, cells from each donor were also treated with a panel of TLR agonists from Invivogen. Within the anaerobic chamber, microbe-cell co-culture plates were loaded into a small anaerobic box and flushed with 1% O2. The plate-containing boxes were incubated in the 37C incubator for 24hr. After 24hr, plates were removed from the incubator. Supernatants were collected and stored at 80C until cytokine analysis was carried out. Cytokine analysis of Human CD11b+ Cell– Microbe Co-culture Supernatants

[156] The standard Luminex MagPix protocol (EMD Millipore) for cytokine analysis was carried out according to manufacturer’s instructions to assess cytokines in supernatant (IL-6, IL-10, TNFa, IL-1b, IL-12p70, CXCL10, IL-12p40, IL-17, IFNg, GM-CSF). Cytokines assessed are listed in Table 8.

Table 8: Human Cytokines Assessed

[157] As seen in Figure 2, Blautia strain A (Deposit Number PTA-125134) and

Bifidobacterium animalis ssp. lactis Strain A (ATCC Deposit Number PTA-125097) induced significantly higher levels of IP-10 and higher ratios of IP-10 to GM-CSF compared to three control bacteria strains that are not therapeutically effective for the treatment of cancer. Control Strain A is a therapeutically ineffective Bifidobacterium bifidum strain. Control Strain B is a therapeutically ineffective Bifidobacterium sp. strain. Control Strain C is also a therapeutically ineffective Bifidobacterium bifidum strain. Example 3: Orally Administered Blautia Strain A inhibits colorectal carcinoma tumor growth

[158] Female 6-8 week old Balb/c mice were obtained from Taconic (Germantown, NY).100,000 CT-26 colorectal tumor cells (ATCC CRL-2638) were resuspended in sterile PBS and inoculated in the presence of 50% Matrigel. CT-26 tumor cells were subcutaneously injected into one hind flank of each mouse. When tumor volumes reached an average of 100mm 3 (approximately 10-12 days following tumor cell inoculation), animals were distributed into the following groups: 1) Vehicle + PBS; 2) anti-PD-1 antibody; and 3) Blautia Strain A (ATCC Deposit Number PTA-125134). Antibodies were administered intraperitoneally (i.p.) at

100ug/mouse (100ul final volume) every four days, starting on day 1, and Blautia Strain A bacteria (5.5x10 4 ) were administered by oral gavage (p.o.) daily, starting on day 1 until the conclusion of the study. The Blautia Strain A group showed tumor growth inhibition comparable to that seen in the anti-PD-1 group (Figures 3 and 4). Example 4: Blautia Strain A in a mouse melanoma model

[159] Female 6-8 week old C57Bl/6 mice were obtained from Taconic (Germantown, NY).100,000 B16-F10 (ATCC CRL-6475) tumor cells were resuspended in sterile PBS containing 50% Matrigel and inoculated in a 100ul final volume into one hind flank (the first flank) of each mouse. Animals were distributed into the following groups: 1) Vehicle + PBS; 2) anti-PD-L1 antibody; and 3) Blautia Strain A (ATCC Deposit Number PTA-125134). Antibodies were administered intraperitoneally (i.p.) at 100ug/mouse (100ul final volume) every four days, starting on day 1, and Blautia Strain A bacteria (6.1x10 7 ) were administered by oral gavage (p.o.) daily, starting on day 1 until the conclusion of the study. The Blautia Strain A group showed better tumor growth inhibition compared to that seen in the anti-PD-L1 group (Figures 5 and 6). Example 5: Orally Administered Bifidobacterium animalis ssp. lactis Strain A inhibits colorectal carcinoma tumor growth

[160] Female 6-8 week old Balb/c mice were obtained from Taconic (Germantown, NY).100,000 CT-26 colorectal tumor cells (ATCC CRL-2638) were resuspended in sterile PBS and inoculated in the presence of 50% Matrigel. CT-26 tumor cells were subcutaneously injected into one hind flank of each mouse. When tumor volumes reached an average of 100mm 3 (approximately 10-12 days following tumor cell inoculation), animals were distributed into the following groups: 1) Vehicle + isotype control antibody IgG2a; and 3) Bifidobacterium animalis ssp. lactis Strain A (ATCC Deposit Number PTA-125097) + IgG2a. Bifidobacterium animalis ssp. lactis bacteria (1x10 9 ) were administered by oral gavage (p.o.) daily, starting on day 1 until the conclusion of the study. The Bifidobacterium animalis ssp. lactis + IgG2a group showed significant tumor growth inhibition compared to the vehicle + IgG2a group (See Figure 7). Example 6: Orally Administered Bifidobacterium animalis ssp. lactis Strain A inhibits colorectal carcinoma tumor growth comparable to inhibition seen with anti-PD-1 treatment

[161] CT-26 tumor cells were subcutaneously injected into one hind flank of each Balb/c mouse as above. When tumor volumes reached an average of 100mm 3 (approximately 10- 12 days following tumor cell inoculation), animals were distributed into the following groups: 1) Vehicle + PBS; 2) Vehicle + isotype control antibody IgG2a; and 3) Vehicle + anti-PD-1; 4) Bifidobacterium animalis ssp. lactis Strain A (ATCC Deposit Number PTA-125097) + IgG2a; and 5) Bifidobacterium animalis ssp. lactis Strain A + anti-PD-1. Antibodies were administered intraperitoneally (i.p.) at 100ug/mouse (100ul final volume) every four days, starting on day 1, and Bifidobacterium animalis ssp. lactis bacteria (1x10 9 ) were administered by oral gavage (p.o.) daily, starting on day 1 until the conclusion of the study. The Bifidobacterium animalis ssp. lactis + IgG2a group showed tumor growth inhibition comparable to that seen in the vehicle + anti-PD- 1 group (See Figure 8). Example 7: Treatment of colorectal carcinoma using different Bifidobacterium animalis ssp. lactis strains

[162] As described in Examples 2 and 3, CT-26 tumor cells were subcutaneously injected into one hind flank of mice and animals were assigned into groups receiving the following treatments: 1) Vehicle; 2) Bifidobacterium animalis ssp. lactis Strain A (ATCC Deposit Number PTA-125097); 3) B. animalis lactis Strain B; 4) B. animalis ssp. lactis Strain C; and 5) anti-PD-1.1x10 9 bacterial cells were administered daily (p.o.), beginning on day 1 of animal group assignment, and tumors measured as described above. Anti-PD-1 antibodies were administered intraperitoneally (i.p.) at 100ug/mouse (100ul final volume) every four days, starting on day 1. As seen in Table 1, Strain A showed significant tumor growth inhibition compared to the other B. animalis lactis treatment groups (Table 9).

Table 9. Colorectal carcinoma tumor volume (mm 3 ) on Day 22 (12 th day of dosing)

Example 8: Intratumorally administered Bifidobacterium animalis ssp. lactis inhibits colorectal carcinoma tumor growth

[163] CT-26 tumor cells were subcutaneously injected into one hind flank of mice and animals were assigned into groups receiving the following treatments: 1) Vehicle; 2)

Bifidobacterium animalis ssp. lactis Strain A (ATCC Deposit Number PTA-125097); and 3) anti-PD-1.2x10 9 bacterial cells were administered intratumorally (IT) on day 1 of animal group assignment, and tumors measured as described above. Mice received a second dose on day 4. Anti-PD-1 antibodies were administered intraperitoneally (i.p.) at 100ug/mouse (100ul final volume) every four days, starting on day 1. The Bifidobacterium animalis ssp. lactis Strain A group showed significant tumor growth inhibition compared to the control group (See Figure 9). Example 9: Testing Bacteria for Induction of Cytokine Expression by Human Macrophages Materials

[164] In addition to testing bacteria for induction of cytokine expression by human macrophages as in Example 1, Paraclostridium benzoelyticum, Agathobaculum sp, and

Turicibacter sanguinis were compared to therapeutically ineffective strains. The macrophage assay was performed as described in Example 1 but with a different sample size (n=6 donors).

[165] As seen in Figure 10, Paraclostridium benzoelyticum, Agathobaculum sp, and Turicibacter sanguinis induced significantly higher ratios of IP-10 to IL-10 compared to two control bacteria strains that are not therapeutically effective for the treatment of cancer (Strain Y and Strain Z). Control Strain Y is a therapeutically ineffective Bacteroides ovatus strain. Control Strain Z is a therapeutically ineffective Clostridium symbiosum strain. Incorporation by Reference

[166] All publications patent applications mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. Equivalents

[167] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.