received by the International Bureau on 21 June 2017 (21.06.2017)

What is claimed is:

1. A method of generating a recombinant virus, comprising:

identifying a patient-specific cancer-related neoepitope of a patient;

determining binding of the neoepitope to an HLA-type of the same patient, and

determining an expression level of the neoepitope;

selecting at least one co-stimulatory molecule; and

genetically modifying a virus to include a nucleic acid encoding the at least one co- stimulatory molecule and the cancer-related neoepitope.

2. The method of claim 1 wherein the virus is an adenovirus.

3. The method of anyone of the preceding claims wherein the virus is replication deficient.

4. The method of anyone of the preceding claims wherein the virus is non-immunogenic.

5. The method of anyone of the preceding claims wherein the cancer-related neoepitope of the patient is identified in silico by location-guided synchronous alignment of omics data of tumor and matched normal samples.

6. The method of anyone of the preceding claims further comprising a step of predicting the HLA type of the patient in silico.

7. The method of anyone of the preceding claims wherein the expression level is at least 20% compared to a matched normal sample.

8. The method of anyone of the preceding claims wherein the co-stimulatory molecule is selected from the group of B7.1 (CD80), B7.2 (CD86), CD30L, CD40, CD40L, CD48, CD70, CD112, CD155, ICOS-L, 4-1BB, GITR-L, LIGHT, TIM3, TIM4, ICAM-1, and LFA3 (CD58).

9. The method of anyone of the preceding claims wherein the nucleic acid further comprises a sequence encoding a cytokine.

10 The method of claim 9 wherein the cytokine is selected from the group consisting of IL-2, IL-7, IL-12, IL-15, an IL-15 superagonist (IL-15N72D), and an IL-15 superagonist/IL- 15RaSushi-Fc fusion complex.

11. The method of anyone of the preceding claims wherein the nucleic acid further comprises a sequence encoding at least one component of a SMAC (supramolecular activation cluster).

12. The method of claim 11 wherein the at least one component of the SMAC is selected form the group consisting of CD2, CD4, CD8, CD28, Lck, Fyn, LFA-1 ,CD43 , and CD45 or their respective binding counterparts.

13. The method of anyone of the preceding claims wherein the nucleic acid further comprises a sequence encoding an activator of a STING (Stimulator of Interferon Gene) pathway.

14. The method of claim 13 wherein the activator of the STING pathway comprises a

chimeric protein in which a transmembrane domain of LMPl of EBV is fused to a signaling domain of IPS- 1.

15. The method of anyone of the preceding claims further comprising a step of including into the nucleic acid a segment that encodes at least a second and distinct cancer-related neoepitope,

16. The method of any one of the preceding claims, further comprising a step of culturing the genetically modified virus to obtain at least 10⁴ virus particles.

17. The method of any one of the preceding claims, further comprising a step of culturing the genetically modified virus to obtain at least 10⁷ virus particles.

18. The method of claim 1 wherein the virus is replication deficient.

19. The method of claim 1 wherein the virus is non-immunogenic.

20. The method of claim 1 wherein the cancer-related neoepitope of the patient is identified in silico by location-guided synchronous alignment of omics data of tumor and matched normal samples.

21. The method of claim 1 further comprising a step of predicting the HLA type of the patient in silico.

22. The method of claim 1 wherein the expression level is at least 20% compared to a

matched normal sample.

23. The method of claim 1 wherein the co-stimulatory molecule is selected from the group of B7.1 (CD80), B7.2 (CD86), CD30L, CD40, CD40L, CD48, CD70, CD112, CD155, ICOS-L, 4-1BB, GITR-L, LIGHT, ΤΓΜ3, TIM4, ICAM-1, and LFA3 (CD58).

24. The method of claim 1 wherein the nucleic acid further comprises a sequence encoding a cytokine.

25. The method of claim 24 wherein the cytokine is selected from the group consisting of IL- 2, IL-7, IL-12, IL-15, an IL-15 superagonist (IL-15N72D), and an IL-15 superagonist/IL- 15RaSushi-Fc fusion complex.

26. The method of claim 1 wherem the nucleic acid further comprises a sequence encoding at least one component of a SMAC (supramolecular activation cluster).

27. The method of claim 26 wherein the at least one component of the SMAC is selected form the group consisting of CD2, CD4, CD8, CD28, Lck, Fyn, LFA-1,CD43, and CD45 or their respective binding counterparts.

28. The method of claim 1 wherein the nucleic acid further comprises a sequence encoding an activator of a STING (Stimulator of Interferon Gene) pathway.

29. The method of claim 28 wherein the activator of the STING pathway comprises a

chimeric protein in which a transmembrane domain of LMP1 of EBV is fused to a signaling domain of IPS- 1.

30. The method of claim 1 further comprising a step of including into the nucleic acid a segment that encodes at least a second distinct disease-related neoepitope.

31. The method of claim 1 further comprising a step of culturing the genetically modified virus to obtain at least 10⁴ virus particles.

32. The method of claim 1 further comprising a step of culturing the genetically modified virus to obtain at least 10^? virus particles.

33. A recombinant virus, comprising a nucleic acid encoding an HLA-matched patient- specific cancer neoepitope and a co-stimulatory molecule functionally coupled to a promoter for expressing the neoepitope and the co-stimulatory molecule in a cell infected with the recombinant virus

34. The recombinant virus of claim 33 wherein the nucleic acid further comprises a segment that encodes at least a second distinct disease-related neoepitope.

35. The recombinant virus of any one of claims 33-34 wherein the co-stimulatory molecule is selected from the group of B7.1 (CD80), B7.2 (CD86), CD30L, CD40, CD40L, CD48, CD70, CD112, CD155, ICOS-L, 4-1BB, GITR-L, LIGHT, TIM3, TIM4, ICAM-1, and LFA3 (CD58).

36. The recombinant virus of any one of claims 33-35 wherein the nucleic acid further

comprises a sequence encoding a cytokine.

37. The recombinant virus of claim 36 wherein the cytokine is selected from the group

consisting of IL-2, IL-7, IL-12, IL-15, an IL-15 superagonist (IL-15N72D), and an IL-15 superagonist/IL-15RaSushi-Fc fusion complex.

38. The recombinant virus of any one of claims 33-37 wherein the nucleic acid further

comprises a sequence encoding at least one component of a SMAC (supramolecular activation cluster).

39. The recombinant virus of claim 38 wherein the at least one component of the SMAC is selected form the group consisting of CD2, CD4, GD8, CD28, Lck, Fyn, LFA-1,CD43, and CD45 or their respective binding counterparts.

40. The recombinant virus of any one of claims 33-39 wherein the nucleic acid further

comprises a sequence encoding an activator of a STING (Stimulator of Interferon Gene) pathway.

41. The recombinant virus of claim 40 wherein the activator of the STING pathway

comprises a chimeric protein in which a transmembrane domain of LMP 1 of EBV is fused to a signaling domain of IPS-1.

42. The recombinant virus of any one of claims 33-41 wherein the virus is an adenovirus.

43. The recombinant virus of claim 42 wherein the adenovirus is an

44. The recombinant virus of claim 33 wherein the co-stimulatory molecule is selected from the group of B7.1 (CD80), B7.2 (CD86), CD30L, CD40, CD40L, CD48, CD70, CD112, CD 155, ICOS-L, 4- IBB, GITR-L, LIGHT, TIM3, TIM4, ICAM-1, and LFA3 (CD58).

45. The recombinant virus of claim 33 wherein the nucleic acid further comprises a sequence encoding a cytokine.

46. The recombinant virus of claim 45 wherein the cytokine is selected from the group

consisting of IL-2, IL-7, ILA2, IL-15, an IL-15 superagonist (IL-15N72D), and an IL-15 superagonist/IL-15RaSushi-Fc fusion complex.

47. The recombinant virus of claim 33 wherein the nucleic acid further comprises a sequence encoding at least one component of a SMAC (supramolecular activation cluster).

48. The recombinant virus of claim 47 wherein the at least one component of the SMAC is selected form the group consisting of CD2, CD4, CD8, CD28, Lck, Fyn, LFA-1,CD43, and CD45 or their respective binding counterparts.

49. The recombinant virus of claim 33 wherein the nucleic acid further comprises a sequence encoding an activator of a STTNG (Stimulator of Interferon Gene) pathway.

50. The recombinant virus of claim 49 wherein the activator of the STING pathway

comprises a chimeric protein in which a transmembrane domain of LMP 1 of EB V is fused to a signaling domain of IPS-1.

51. The recombinant virus of claim 33 wherein the virus is an adenovirus.

52. The recombinant virus of claim 51 wherein the adenovirus is an

53. A pharmaceutical composition comprising a recombinant virus according to any one of claims 44-52.

54. The pharmaceutical composition of claim 53 further comprising a second and distinct virus according to any one of claims 44-52.

55. Use of a recombinant virus according to any one of claims 44-52 in a treatment of a cancer.

56. A method of treating a patient, comprising:

obtaining a tumor sample and a matched normal sample from the patient;

identifying an HLA-type of the patient and identifying a patient-specific cancer- related neoepitope of the same patient; genetically modifying a virus to include (i) a nucleic acid encoding the neoepitope when the binding affinity is below a predetermined threshold value, and (ii) a nucleic acid encoding at least one co-stimulatory molecule; and administering the genetically modified virus to the patient.

57. The method of claim 56 wherein the steps of identifying the HLA-type and identifying the cancer-related neoepitope of the patient is performed in silica using genomic information from the tumor sample and the matched normal sample.

58. The method of claim 56 wherein the co-stimulatory molecule is selected from the group of B7.1 (CD80), B7.2 (CD86), CD30L, CD40, CD40L, CD48, CD70, CD112, CD155, ICOS-L, 4-1BB, GITR-L, LIGHT, TIM3, TIM4, ICAM-1, and LP A3 (CD58).

59. The method of claim 56 wherein the virus further comprises a nucleic acid encoding a cytokine.

60. The method of claim 59 wherein the cytokine is selected from the group consisting of IL- 2, IL-7, IL-12, IL-15, an IL-15 superagonist (IL-15N72D), and an IL-15 superagonist/IL- 15RaSushi-Fc fusion complex.

61. The method of claim 56 wherein the virus further comprises a nucleic acid encoding at least one component of a SMAC (supramolecular activation cluster).

62. The method of claim 61 wherein the at least one component of the SMAC is selected form the group consisting of CD2, CD4, CD8, CD28, Lck, Fyn, LFA-1,CD43, and CD45 or their respective binding counterparts.

63. The method of claim 56 wherein the virus further comprises a nucleic acid encoding an activator of a STING (Stimulator of Interferon Gene) pathway.

64. The method of claim 63 wherein the activator of the STING pathway comprises a

chimeric protein in which a transmembrane domain of LMPl of EBV is fused to a signaling domain of IPS- 1.

65. The method of claim 56 wherein the virus is an adenovirus.

66. The method of claim 65 wherein the adenovirus is an

67. The method of claim 56 wherein the virus further comprises a nucleic acid encoding at least one additional cancer-related neoepitope.

68. The method of claim 56 further comprising a step of administering an immune checkpoint inhibitor.

69. The method of claim 56 wherein the genetically modified virus is administered via

subcutaneous or intratumoral injection.