GOODRIDGE JODE (US)
BJORDAHL RYAN (US)
WO2019112899A2 | 2019-06-13 |
US20200069734A1 | 2020-03-05 | |||
US20160009813A1 | 2016-01-14 |
WANG WENXIU; JIANG JINGTING; WU CHANGPING: "CAR-NK for tumor immunotherapy: Clinical transformation and future prospects", CANCER LETTERS, NEW YORK, NY, US, vol. 472, 29 November 2019 (2019-11-29), US , pages 175 - 180, XP086018006, ISSN: 0304-3835, DOI: 10.1016/j.canlet.2019.11.033
See also references of EP 4168538A4
CLAIMS What is claimed is: 1. A composition comprising two or more synthetic cell populations, wherein the composition comprises: (i) a first synthetic cell population comprising iPSC-derived NK cells, wherein the iPSC- derived NK cells comprise: (a) an exogenous CD16 or a variant thereof; and (b) one or both of (i) a first chimeric antigen receptor (CAR), and (ii) a partial or full length peptide of a cell surface expressed exogenous cytokine and/or a receptor thereof; and (ii) a second synthetic cell population comprising iPSC-derived T cells, wherein the iPSC-derived T cells comprise: at least a second chimeric antigen receptor (CAR), and wherein the second CAR is expressed under control of an endogenous promoter of a TCR locus. 2. The composition of claim 1, wherein the exogenous CD16 or variant thereof is a high affinity non-cleavable exogenous CD16 (hnCD16); or wherein the exogenous CD16 or variant thereof comprises at least one of: (a) F176V and S197P in ectodomain domain of CD16; (b) a full or partial ectodomain originated from CD64; (c) a non-native (or non-CD16) transmembrane domain; (d) a non-native (or non-CD16) intracellular domain; (e) a non-native (or non-CD16) signaling domain; (f) a non-native stimulatory domain; and (g) transmembrane, signaling, and stimulatory domains that are not originated from CD16, and are originated from a same or different polypeptide. 3. The composition of claim 2, wherein: (a) the non-native transmembrane domain is derived from CD3D, CD3E, CD3G, CD3ζ, CD4, CD8, CD8a, CD8b, CD27, CD28, CD40, CD84, CD166, 4-1BB, OX40, ICOS, ICAM-1, CTLA-4, PD-1, LAG-3, 2B4, BTLA, CD16, IL7, IL12, IL15, KIR2DL4, KIR2DS1, NKp30, NKp44, NKp46, NKG2C, NKG2D, or T cell receptor (TCR) polypeptide; (b) the non-native stimulatory domain is derived from CD27, CD28, 4-1BB, OX40, ICOS, PD-1, LAG-3, 2B4, BTLA, DAP10, DAP12, CTLA-4, or NKG2D polypeptide; (c) the non-native signaling domain is derived from CD3ζ, 2B4, DAP10, DAP12, DNAM1, CD137 (4-1BB), IL21, IL7, IL12, IL15, NKp30, NKp44, NKp46, NKG2C, or NKG2D polypeptide; or (d) the non-native transmembrane domain is derived from NKG2D, the non-native stimulatory domain is derived from 2B4, and the non-native signaling domain is derived from CD3ζ. 4. The composition of claim 1, wherein the first CAR and the second CAR are the same or are different in targeting specificity, and wherein the first CAR or the second CAR is: (i) T cell specific or NK cell specific; (ii) a bi-specific antigen binding CAR; (iii) a switchable CAR; (iv) a dimerized CAR; (v) a split CAR; (vi) a multi-chain CAR; (vii) an inducible CAR; (viii) co-expressed with another CAR; (ix) co-expressed with a partial or full length peptide of a cell surface expressed exogenous cytokine and/or a receptor thereof, optionally in separate constructs or in a bi- cistronic construct; (x) co-expressed with a checkpoint inhibitor, optionally in separate constructs or in a bi-cistronic construct; (xi) specific to CD19 or BCMA; and/or (xii) specific to any one of ADGRE2, carbonic anhydrase IX (CAIX), CCR1, CCR4, carcinoembryonic antigen (CEA), CD3, CD5, CD7, CD8, CD10, CD20, CD22, CD30, CD33, CD34, CD38, CD41, CD44, CD44V6, CD49f, CD56, CD70, CD74, CD99, CD123, CD133, CD138, CDS, CLEC12A, an antigen of a cytomegalovirus (CMV) infected cell, epithelial glycoprotein2 (EGP-2), epithelial glycoprotein-40 (EGP-40), epithelial cell adhesion molecule (EpCAM), EGFRvIII, receptor tyrosine-protein kinases erb-B2,3,4, EGFIR, EGFR-VIII, ERBB folate-binding protein (FBP), fetal acetylcholine receptor (AChR), folate receptor-a, Ganglioside G2 (GD2), Ganglioside G3 (GD3), human Epidermal Growth Factor Receptor 2 (HER-2), human telomerase reverse transcriptase (hTERT), ICAM-1, Integrin B7, Interleukin-13 receptor subunit alpha-2 (IL-13Rα2), κ-light chain, kinase insert domain receptor (KDR), Lewis A (CA19.9), Lewis Y (LeY), L1 cell adhesion molecule (L1-CAM), LILRB2, melanoma antigen family A 1 (MAGE-A1), MICA/B, Mucin 1 (Muc-1), Mucin 16 (Muc-16), Mesothelin (MSLN), NKCSI, NKG2D ligands, c-Met, cancer-testis antigen NY-ESO-1, oncofetal antigen (h5T4), PRAME, prostate stem cell antigen (PSCA), PRAME prostate-specific membrane antigen (PSMA), tumor- associated glycoprotein 72 (TAG-72), TIM-3, TRBC1, TRBC2, vascular endothelial growth factor R2 (VEGF- R2), Wilms tumor protein (WT-1), and a pathogen antigen. 5. The composition of claim 1, wherein the partial or full length peptide of a cell surface expressed exogenous cytokine and/or a receptor thereof: (a) comprises at least one of IL2, IL4, IL6, IL7, IL9, IL10, IL11, IL12, IL15, IL18, IL21, and/or respective receptors thereof; or (b) comprises at least one of: (i) co-expression of IL15 and IL15Rα by using a self-cleaving peptide; (ii) a fusion protein of IL15 and IL15Rα; (iii) an IL15/IL15Rα fusion protein with intracellular domain of IL15Rα truncated; (iv) a fusion protein of IL15 and membrane bound Sushi domain of IL15Rα; (v) a fusion protein of IL15 and IL15Rβ; (vi) a fusion protein of IL15 and common receptor γC, wherein the common receptor γC is native or modified; and (vii) a homodimer of IL15Rβ; wherein any one of (i)-(vii) can be co-expressed with a CAR in separate constructs or in a bi-cistronic construct; and optionally, (c) is transiently expressed. 6. The composition of claim 1, wherein the iPSC-derived NK cells and/or the iPSC-derived T cells further comprise one or more of: (i) HLA-I deficiency; (ii) HLA-II deficiency; (iii) introduced expression of HLA-G or non-cleavable HLA-G; (iv) at least one of lig-, inR+, cs-CD3+, En+, and Ab+; wherein (1) lig- is negative in an expressed alloantigen; (2) inR+ is positive in an expressed inactivation-CAR corresponding to the negative alloantigen; (3) cs-CD3+ is positive in cell surface expressed CD3; (4) En+ is positive in at least one expressed engager, wherein the engager comprises a bi-specific T cell engager (BiTE), or a tri-specific killer cell engager (TriKE); and (5) Ab+ is positive in at least one expressed antibody or checkpoint inhibitor; (v) deletion or reduced expression in at least one of B2M, CIITA, TAP1, TAP2, Tapasin, NLRC5, PD1, LAG3, TIM3, RFXANK, RFX5, RAG1, RFXAP, and any gene in the chromosome 6p21 region; and (vi) introduced or increased expression in at least one of HLA-E, HLA-G, 41BBL, CD4, CD8, CD16, CD47, CD113, CD131, CD137, CD80, PDL1, A2AR, TCR, Fc receptor, and surface triggering receptor for coupling with bi- or multi- specific or universal engagers. 7. The composition of claim 6, wherein: (i) the alloantigen comprises CD40L, OX40, or 4-1BB; (ii) the inactivation-CAR comprises CD40L-CAR, OX40-CAR, or 4-1BB-CAR; (iii) the BiTE or the TriKE recognizes (a) an immune cell surface molecule comprising CD3, CD28, CD5, CD16, NKG2D, CD64, CD32, CD89, NKG2C, or a chimeric Fc receptor thereof; and (b) a tumor surface molecule comprising B7H3, BCMA, CD10, CD19, CD20, CD22, CD24, CD30, CD33, CD34, CD38, CD44, CD79a, CD79b, CD123, CD138, CD179b, CEA, CLEC12A, CS-1, DLL3, EGFR, EGFRvIII, EPCAM, FLT-3, FOLR1, FOLR3, GD2, gpA33, HER2, HM1.24, LGR5, MSLN, MCSP, MICA/B, PSMA, PAMA, P-cadherin, or ROR1; (iv) the BiTE comprises CD3-CD19, CD16-CD30, CD64-CD30, CD16-BCMA, CD64- BCMA, or CD3-CD33; (v) the TriKE comprises CD16-IL15-EPCAM, CD64-IL15-EPCAM, CD16-IL15-CD33, CD64-IL15-CD33, or NKG2C-IL15-CD33; (vi) the antibody comprises an anti-CD20, anti-HER2, anti-CD52, anti-EGFR, anti- CD123, anti-GD2, anti-PDL1, or anti-CD38 antibody; or (vii) the checkpoint inhibitor comprises (a) an antagonist to a checkpoint molecule comprising PD-1, PDL-1, TIM-3, TIGIT, LAG-3, CTLA-4, 2B4, 4-1BB, 4-1BBL, A2AR, BATE, BTLA, CD39, CD47, CD73, CD94, CD96, CD160, CD200, CD200R, CD274, CEACAM1, CSF-1R, Foxpl, GARP, HVEM, IDO, EDO, TDO, LAIR-1, MICA/B, NR4A2, MAFB, OCT-2, Rara (retinoic acid receptor alpha), TLR3, VISTA, NKG2A/HLA-E, or inhibitory KIR; (b) one of atezolizumab, avelumab, durvalumab, ipilimumab, IPH4102, IPH43, IPH33, lirimumab, monalizumab, nivolumab, pembrolizumab, and their derivatives or functional equivalents; or (c) one of atezolizumab, nivolumab, and pembrolizumab. 8. The composition of claim 1, wherein the iPSC-derived NK cells or the iPSC-derived T cells comprise: (i) one or more exogenous polynucleotides integrated in one desired integration site; or (ii) more than two exogenous polynucleotides integrated in different desired integration sites. 9. The composition of claim 8, wherein the desired integration site comprises at least one of AAVS1, CCR5, ROSA26, collagen, HTRP, H11, GAPDH, RUNX1, B2M, TAP1, TAP2, tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR α or β constant region, NKG2A, NKG2D, CD25, CD38, CD40L, CD44, CD54, CD56, CD58, CD69, CD71, OX40, 4-1BB, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, and TIGIT. 10. The composition of claim 8, wherein the desired integration site comprises TCR α or β constant region, CD25, CD38, CD40L, CD44, CD54, CD58, CD69, CD71, OX40 or 4-1BB; and optionally, wherein the TCRα or TCRβ, CD25, CD38, CD40L, CD44, CD54, CD58, CD69, CD71, OX40 or 4-1BB is knocked out as a result of integrating said one or more exogenous polynucleotides at the respective integration site. 11. The composition of claim 1, wherein the iPSC-derived NK cells or the iPSC-derived T cells have at least one of the following characteristics comprising: (i) improved persistency and/or survival, (ii) increased resistance to native immune cells, (iii) increased cytotoxicity, (iv) improved tumor penetration, (v) enhanced or acquired ADCC, (vi) enhanced ability in migrating, and/or activating or recruiting bystander immune cells to tumor sites; (vii) enhanced ability to reduce tumor immunosuppression, and (viii) improved ability in rescuing tumor antigen escape, in comparison to its native counterpart cell obtained from peripheral blood, umbilical cord blood, or any other donor tissues. 12. The composition of claim 1, wherein the iPSC-derived NK cells or the iPSC-derived T cells comprise longer telomeres in comparison to their respective native counterpart cell obtained from peripheral blood, umbilical cord blood, or any other donor tissues. 13. The composition of claim 1, wherein the first synthetic cell population or the second synthetic cell population is modulated ex vivo. 14. The composition of claim 13, wherein the modulated first synthetic cell population comprising iPSC-derived NK cells comprises an increased number or ratio of type I NKT cells, and/or adaptive NK cells, as compared to the first synthetic cell population without being modulated; or wherein the second modulated synthetic cell population comprising iPSC- derived T cells comprises an increased number or ratio of naïve T cells, stem cell memory T cells, and/or central memory T cells, as compared to the second synthetic cell population without being modulated. 15. The composition of claim 1, wherein (i) the iPSC-derived NK cells and the iPSC-derived T cells are in a ratio ranging from 100:1 to 1:100; (ii) the composition further comprises one or more additional cell populations; or (iii) the composition further comprises one or more therapeutic agents. 16. The composition of claim 15, wherein the additional cell population comprises regulatory cells. 17. The composition of claim 16, wherein the regulatory cells are iPSC-derived immune regulatory cells or myeloid derived suppressor cells (MDSCs). 18. The composition of claim 15, wherein the one or more therapeutic agents comprise a peptide, a cytokine, a checkpoint inhibitor, a mitogen, a growth factor, a small RNA, a dsRNA (double stranded RNA), mononuclear blood cells, feeder cells, feeder cell components or replacement factors thereof, a vector comprising one or more polynucleic acids of interest, an antibody, a chemotherapeutic agent or a radioactive moiety, or an immunomodulatory drug (IMiD). 19. The composition of claim 18, wherein the checkpoint inhibitor comprises: (a) one or more antagonist checkpoint molecules comprising PD-1, PDL-1, TIM-3, TIGIT, LAG-3, CTLA-4, 2B4, 4-1BB, 4-1BBL, A2AR, BATE, BTLA, CD39, CD47, CD73, CD94, CD96, CD160, CD200, CD200R, CD274, CEACAM1, CSF-1R, Foxpl, GARP, HVEM, IDO, EDO, TDO, LAIR-1, MICA/B, NR4A2, MAFB, OCT-2, Rara (retinoic acid receptor alpha), TLR3, VISTA, NKG2A/HLA-E, or inhibitory KIR; (b) one or more of atezolizumab, avelumab, durvalumab, ipilimumab, IPH4102, IPH43, IPH33, lirimumab, monalizumab, nivolumab, pembrolizumab, and their derivatives or functional equivalents; or (c) at least one of atezolizumab, nivolumab, and pembrolizumab. 20. The composition of claim 18, wherein the antibody comprises: (a) anti-CD20, anti-HER2, anti-CD52, anti-EGFR, anti-CD123, anti-GD2, anti-PDL1, and/or anti-CD38 antibody; (b) one or more of retuximab, veltuzumab, ofatumumab, ublituximab, ocaratuzumab, obinutuzumab, trastuzumab, pertuzumab, alemtuzumab, certuximab, dinutuximab, avelumab, daratumumab, isatuximab, MOR202, 7G3, CSL362, elotuzumab, and their humanized or Fc modified variants or fragments and their functional equivalents and biosimilars; or (c) daratumumab. 21. The composition of claim 1, wherein the first synthetic cell population and the second synthetic cell population are separate populations or are combined into a mixed population. 22. Therapeutic use of the composition of any one of the claims 1-21 by introducing the composition to a subject suitable for adoptive cell therapy, wherein the subject has an autoimmune disorder; a hematological malignancy; a solid tumor; cancer, or a virus infection. 23. A method of improving tumor killing and/or clearance by a population of CAR-T cells comprising: providing a synthetic cell population comprising iPSC-derived NK cells to the population of CAR-T cells to obtain a combined cell population, wherein the iPSC-derived NK cells comprise: (a) an exogenous CD16 or a variant thereof; and (b) one or both of (i) a first chimeric antigen receptor (CAR), and (ii) a partial or full length peptide of a cell surface expressed exogenous cytokine and/or a receptor thereof; and wherein the first CAR of the iPSC-derived NK cells comprise a CAR targeting specificity that is same or different from that of the CAR-T cell. 24. The method of claim 23, wherein the combined cell population comprises cells having at least one of the following characteristics comprising: (i) improved persistency and/or survival, (ii) increased resistance to native immune cells, (iii) increased cytotoxicity, (iv) improved tumor penetration, (v) enhanced or acquired ADCC, (vi) enhanced ability in migrating, and/or activating or recruiting bystander immune cells to tumor sites; (vii) enhanced ability to reduce tumor immunosuppression, and (viii) improved ability in rescuing tumor antigen escape, in comparison to tumor killing and/or clearance by the population of CAR-T cells only without the combination of the iPSC-derived NK cells. 25. The method of claim 23, wherein the exogenous CD16 or variant thereof is a high affinity non-cleavable exogenous CD16 (hnCD16); or wherein the exogenous CD16 or variant thereof comprises at least one of: (a) F176V and S197P in ectodomain domain of CD16; (b) a full or partial ectodomain originated from CD64; (c) a non-native (or non-CD16) transmembrane domain; (d) a non-native (or non-CD16) intracellular domain; (e) a non-native (or non-CD16) signaling domain; (f) a non-native stimulatory domain; and (g) transmembrane, signaling, and stimulatory domains that are not originated from CD16, and are originated from a same or different polypeptide. 26. The method of claim 25, wherein (a) the non-native transmembrane domain is derived from CD3D, CD3E, CD3G, CD3ζ, CD4, CD8, CD8a, CD8b, CD27, CD28, CD40, CD84, CD166, 4-1BB, OX40, ICOS, ICAM-1, CTLA-4, PD-1, LAG-3, 2B4, BTLA, CD16, IL7, IL12, IL15, KIR2DL4, KIR2DS1, NKp30, NKp44, NKp46, NKG2C, NKG2D, or T cell receptor (TCR) polypeptide; (b) the non-native stimulatory domain is derived from CD27, CD28, 4-1BB, OX40, ICOS, PD-1, LAG-3, 2B4, BTLA, DAP10, DAP12, CTLA-4, or NKG2D polypeptide; (c) the non-native signaling domain is derived from CD3ζ, 2B4, DAP10, DAP12, DNAM1, CD137 (4-1BB), IL21, IL7, IL12, IL15, NKp30, NKp44, NKp46, NKG2C, or NKG2D polypeptide; or (d) the non-native transmembrane domain is derived from NKG2D, the non-native stimulatory domain is derived from 2B4, and the non-native signaling domain is derived from CD3ζ. 27. The method of claim 23, wherein the partial or full length peptide of a cell surface expressed exogenous cytokine and/or a receptor thereof: (a) comprises at least one of IL2, IL4, IL6, IL7, IL9, IL10, IL11, IL12, IL15, IL18, IL21, and/or respective receptors thereof; or (b) comprises at least one of: (i) co-expression of IL15 and IL15Rα by using a self-cleaving peptide; (ii) a fusion protein of IL15 and IL15Rα; (iii) an IL15/IL15Rα fusion protein with intracellular domain of IL15Rα truncated; (iv) a fusion protein of IL15 and membrane bound Sushi domain of IL15Rα; (v) a fusion protein of IL15 and IL15Rβ; (vi) a fusion protein of IL15 and common receptor γC, wherein the common receptor γC is native or modified; and (vii) a homodimer of IL15Rβ; wherein any one of (i)-(vii) can be co-expressed with a CAR in separate constructs or in a bi-cistronic construct; and optionally, (c) is transiently expressed. 28. The method of claim 23, wherein the CAR-T cells are differentiated from an engineered iPSC, and/or wherein the CAR-T cells comprise a CAR having targeting specificity to any one of ADGRE2, carbonic anhydrase IX (CAIX), CCR1, CCR4, carcinoembryonic antigen (CEA), CD3, CD5, CD7, CD8, CD10, CD20, CD22, CD30, CD33, CD34, CD38, CD41, CD44, CD44V6, CD49f, CD56, CD70, CD74, CD99, CD123, CD133, CD138, CDS, CLEC12A, an antigen of a cytomegalovirus (CMV) infected cell, epithelial glycoprotein2 (EGP-2), epithelial glycoprotein-40 (EGP-40), epithelial cell adhesion molecule (EpCAM), EGFRvIII, receptor tyrosine-protein kinases erb-B2,3,4, EGFIR, EGFR-VIII, ERBB folate-binding protein (FBP), fetal acetylcholine receptor (AChR), folate receptor-a, Ganglioside G2 (GD2), Ganglioside G3 (GD3), human Epidermal Growth Factor Receptor 2 (HER-2), human telomerase reverse transcriptase (hTERT), ICAM-1, Integrin B7, Interleukin-13 receptor subunit alpha-2 (IL- 13Rα2), κ-light chain, kinase insert domain receptor (KDR), Lewis A (CA19.9), Lewis Y (LeY), L1 cell adhesion molecule (L1-CAM), LILRB2, melanoma antigen family A 1 (MAGE-A1), MICA/B, Mucin 1 (Muc-1), Mucin 16 (Muc-16), Mesothelin (MSLN), NKCSI, NKG2D ligands, c-Met, cancer-testis antigen NY-ESO-1, oncofetal antigen (h5T4), PRAME, prostate stem cell antigen (PSCA), PRAME prostate-specific membrane antigen (PSMA), tumor- associated glycoprotein 72 (TAG-72), TIM-3, TRBC1, TRBC2, vascular endothelial growth factor R2 (VEGF- R2), Wilms tumor protein (WT-1), and a pathogen antigen. 29. The method of claim 23, wherein the iPSC-derived NK cells and/or the CAR-T cells further comprise one or more of: (i) HLA-I deficiency; (ii) HLA-II deficiency; (iii) introduced expression of HLA-G or non-cleavable HLA-G; (iv) at least one of lig-, inR+, cs-CD3+, En+, and Ab+; wherein (1) lig- is negative in an expressed alloantigen; (2) inR+ is positive in an expressed inactivation-CAR corresponding to the negative alloantigen; (3) cs-CD3+ is positive in cell surface expressed CD3; (4) En+ is positive in at least one expressed engager, wherein the engager comprises a bi-specific T cell engager (BiTE), or a tri-specific killer cell engager (TriKE); and (5) Ab+ is positive in at least one expressed antibody or checkpoint inhibitor; (v) deletion or reduced expression in at least one of B2M, CIITA, TAP1, TAP2, Tapasin, NLRC5, PD1, LAG3, TIM3, RFXANK, RFX5, RAG1, RFXAP, and any gene in the chromosome 6p21 region; and (vi) introduced or increased expression in at least one of HLA-E, HLA-G, 4-1BBL, CD4, CD8, CD16, CD47, CD113, CD131, CD137, CD80, PDL1, A2AR, TCR, Fc receptor, and surface triggering receptor for coupling with bi- or multi- specific or universal engagers. 30. The method of claim 29, wherein (i) the alloantigen comprises CD40L, OX40, or 4-1BB; (ii) the inactivation-CAR comprises CD40L-CAR, OX40-CAR, or 4-1BB-CAR; (iii) the BiTE or the TriKE recognizes (a) an immune cell surface molecule comprising CD3, CD28, CD5, CD16, NKG2D, CD64, CD32, CD89, NKG2C, or a chimeric Fc receptor thereof; and (b) a tumor surface molecule comprising B7H3, BCMA, CD10, CD19, CD20, CD22, CD24, CD30, CD33, CD34, CD38, CD44, CD79a, CD79b, CD123, CD138, CD179b, CEA, CLEC12A, CS-1, DLL3, EGFR, EGFRvIII, EPCAM, FLT-3, FOLR1, FOLR3, GD2, gpA33, HER2, HM1.24, LGR5, MSLN, MCSP, MICA/B, PSMA, PAMA, P-cadherin, or ROR1; (iv) the BiTE comprises CD3-CD19, CD16-CD30, CD64-CD30, CD16-BCMA, CD64- BCMA, or CD3-CD33; (v) the TriKE comprises CD16-IL15-EPCAM, CD64-IL15-EPCAM, CD16-IL15-CD33, CD64-IL15-CD33, or NKG2C-IL15-CD33; (vi) the antibody comprises an anti-CD20, anti-HER2, anti-CD52, anti-EGFR, anti- CD123, anti-GD2, anti-PDL1, or anti-CD38 antibody; or (vii) the checkpoint inhibitor comprises (a) an antagonist to a checkpoint molecule comprising PD-1, PDL-1, TIM-3, TIGIT, LAG-3, CTLA-4, 2B4, 4-1BB, 4-1BBL, A2AR, BATE, BTLA, CD39, CD47, CD73, CD94, CD96, CD160, CD200, CD200R, CD274, CEACAM1, CSF-1R, Foxpl, GARP, HVEM, IDO, EDO, TDO, LAIR-1, MICA/B, NR4A2, MAFB, OCT-2, Rara (retinoic acid receptor alpha), TLR3, VISTA, NKG2A/HLA-E, or inhibitory KIR; (b) one of atezolizumab, avelumab, durvalumab, ipilimumab, IPH4102, IPH43, IPH33, lirimumab, monalizumab, nivolumab, pembrolizumab, and their derivatives or functional equivalents; or (c) one of atezolizumab, nivolumab, and pembrolizumab. 31. The method of claim 30, further comprising providing one or more therapeutic agents, wherein the one or more therapeutic agents comprise a peptide, a cytokine, a checkpoint inhibitor, an antibody, a mitogen, a growth factor, a small RNA, a dsRNA (double stranded RNA), mononuclear blood cells, feeder cells, feeder cell components or replacement factors thereof, a vector comprising one or more polynucleic acids of interest, a chemotherapeutic agent or a radioactive moiety, or an immunomodulatory drug (IMiD). 32. The method of claim 31, wherein the checkpoint inhibitor comprises: (a) one or more antagonist checkpoint molecules comprising PD-1, PDL-1, TIM-3, TIGIT, LAG-3, CTLA-4, 2B4, 4-1BB, 4-1BBL, A2AR, BATE, BTLA, CD39, CD47, CD73, CD94, CD96, CD160, CD200, CD200R, CD274, CEACAM1, CSF-1R, Foxpl, GARP, HVEM, IDO, EDO, TDO, LAIR-1, MICA/B, NR4A2, MAFB, OCT-2, Rara (retinoic acid receptor alpha), TLR3, VISTA, NKG2A/HLA-E, or inhibitory KIR; (b) one or more of atezolizumab, avelumab, durvalumab, ipilimumab, IPH4102, IPH43, IPH33, lirimumab, monalizumab, nivolumab, pembrolizumab, and their derivatives or functional equivalents; or (c) at least one of atezolizumab, nivolumab, and pembrolizumab. 33. The method of claim 31, wherein the antibody comprises: (a) anti-CD20, anti-HER2, anti-CD52, anti-EGFR, anti-CD123, anti-GD2, anti-PDL1, and/or anti-CD38 antibody; (b) one or more of retuximab, veltuzumab, ofatumumab, ublituximab, ocaratuzumab, obinutuzumab, trastuzumab, pertuzumab, alemtuzumab, certuximab, dinutuximab, avelumab, daratumumab, isatuximab, MOR202, 7G3, CSL362, elotuzumab, and their humanized or Fc modified variants or fragments and their functional equivalents and biosimilars; or (c) daratumumab. 34. A method of treating a subject using the composition of any one of claims 1-21, wherein the method comprises: (I) administering the first synthetic cell population that comprises iPSC-derived NK cells to the subject, wherein the iPSC-derived NK cells comprise: (a) an exogenous CD16 or a variant thereof; and (b) one or both of (i) a first chimeric antigen receptor (CAR), and (ii) a partial or full length peptide of a cell surface expressed exogenous cytokine or a receptor thereof; and (II) administering the second synthetic cell population that comprises iPSC-derived T cells to the subject, wherein the iPSC-derived T cells comprise: at least a second chimeric antigen receptor (CAR), wherein the second CAR is expressed under the control of an endogenous promoter of a TCR locus, and wherein the first CAR and the second CAR are same or different in targeting specificity. 35. The method of claim 34, wherein the subject has a condition comprising an autoimmune disorder; a hematological malignancy; a solid tumor; cancer, or a virus infection; and/or wherein the method provides enhanced improvement of the condition in comparison to using the first or the second synthetic cell population alone. 36. The method of claim 34, wherein the first synthetic cell population and the second synthetic cell population are administrated concurrently, or sequentially in any order. 37. The method of claim 34, further comprising: administering one or more therapeutic agents; and/or administering an additional population of cells; wherein the one or more therapeutic agents and/or the additional population of cells are administered concurrently or sequentially with either the first synthetic cell population or the second synthetic cell population. 38. The method of claim 37, wherein the additional cell population comprises regulatory cells. 39. The method of claim 38, wherein the regulatory cells are iPSC-derived immune regulatory cells or myeloid derived suppressor cells (MDSCs). 40. The method of claim 34, wherein the the first synthetic cell population and the second synthetic cell population are separate populations or are combined into a mixed population prior to administration to the subject. 41. The method of claim 37, wherein the one or more therapeutic agents comprise a peptide, a cytokine, a checkpoint inhibitor, a mitogen, a growth factor, a small RNA, a dsRNA (double stranded RNA), mononuclear blood cells, feeder cells, feeder cell components or replacement factors thereof, a vector comprising one or more polynucleic acids of interest, an antibody, a chemotherapeutic agent or a radioactive moiety, or an immunomodulatory drug (IMiD). 42. The method of claim 34, further comprising administering to the subject: (i) a BiTE or a TriKE specific to (a) an immune cell surface molecule comprising CD3, CD28, CD5, CD16, NKG2D, CD64, CD32, CD89, NKG2C, or a chimeric Fc receptor thereof; and (b) a tumor surface molecule comprising B7H3, BCMA, CD10, CD19, CD20, CD22, CD24, CD30, CD33, CD34, CD38, CD44, CD79a, CD79b, CD123, CD138, CD179b, CEA, CLEC12A, CS-1, DLL3, EGFR, EGFRvIII, EPCAM, FLT-3, FOLR1, FOLR3, GD2, gpA33, HER2, HM1.24, LGR5, MSLN, MCSP, MICA/B, PSMA, PAMA, P-cadherin, or ROR1; (ii) a BiTE comprising CD3-CD19, CD16-CD30, CD64-CD30, CD16-BCMA, CD64- BCMA, or CD3-CD33; (iii) a TriKE comprising CD16-IL15-EPCAM, CD64-IL15-EPCAM, CD16-IL15-CD33, CD64-IL15-CD33, or NKG2C-IL15-CD33; (iv) an antibody comprising an anti-CD20, anti-HER2, anti-CD52, anti-EGFR, anti- CD123, anti-GD2, anti-PDL1, or anti-CD38 antibody; or (v) a checkpoint inhibitor comprising (a) an antagonist to a checkpoint molecule comprising PD-1, PDL-1, TIM-3, TIGIT, LAG-3, CTLA-4, 2B4, 4-1BB, 4-1BBL, A2AR, BATE, BTLA, CD39, CD47, CD73, CD94, CD96, CD160, CD200, CD200R, CD274, CEACAM1, CSF-1R, Foxpl, GARP, HVEM, IDO, EDO, TDO, LAIR-1, MICA/B, NR4A2, MAFB, OCT-2, Rara (retinoic acid receptor alpha), TLR3, VISTA, NKG2A/HLA-E, or inhibitory KIR; (b) one of atezolizumab, avelumab, durvalumab, ipilimumab, IPH4102, IPH43, IPH33, lirimumab, monalizumab, nivolumab, pembrolizumab, and their derivatives or functional equivalents; or (c) one of atezolizumab, nivolumab, and pembrolizumab. 43. A method of manufacturing the composition of claim 1, comprising: (I) differentiating a first genetically engineered iPSC to obtain a first synthetic cell population comprising iPSC-derived NK cells, wherein the first iPSC comprises a polynucleotide encoding (a) an exogenous CD16 or a variant thereof; and (b) one or both of (i) a first chimeric antigen receptor (CAR), and (ii) a partial or full length peptide of a cell surface expressed exogenous cytokine and/or a receptor thereof, wherein the iPSC-derived NK cells comprise (a) and (b); and (II) differentiating a second genetically engineered iPSC to obtain a second synthetic cell population comprising iPSC-derived T cells, wherein the second iPSC comprises a polynucleotide encoding at least a second chimeric antigen receptor (CAR), wherein the second CAR is expressed under the control of an endogenous promoter of a TCR locus, and wherein the iPSC-derived T cells comprise the second CAR, thereby manufacturing the composition of claim 1. 44. The method of claim 43, wherein the exogenous CD16 or variant thereof is a high affinity non-cleavable exogenous CD16 (hnCD16); or wherein the exogenous CD16 or variant thereof comprises at least one of: (a) F176V and S197P in ectodomain domain of CD16; (b) a full or partial ectodomain originated from CD64; (c) a non-native (or non-CD16) transmembrane domain; (d) a non-native (or non-CD16) intracellular domain; (e) a non-native (or non-CD16) signaling domain; (f) a non-native stimulatory domain; and (g) transmembrane, signaling, and stimulatory domains that are not originated from CD16, and are originated from a same or different polypeptide. 45. The method of claim 44, wherein: (a) the non-native transmembrane domain is derived from CD3D, CD3E, CD3G, CD3ζ, CD4, CD8, CD8a, CD8b, CD27, CD28, CD40, CD84, CD166, 4-1BB, OX40, ICOS, ICAM-1, CTLA-4, PD-1, LAG-3, 2B4, BTLA, CD16, IL7, IL12, IL15, KIR2DL4, KIR2DS1, NKp30, NKp44, NKp46, NKG2C, NKG2D, or T cell receptor (TCR) polypeptide; (b) the non-native stimulatory domain is derived from CD27, CD28, 4-1BB, OX40, ICOS, PD-1, LAG-3, 2B4, BTLA, DAP10, DAP12, CTLA-4, or NKG2D polypeptide; (c) the non-native signaling domain is derived from CD3ζ, 2B4, DAP10, DAP12, DNAM1, CD137 (4-1BB), IL21, IL7, IL12, IL15, NKp30, NKp44, NKp46, NKG2C, or NKG2D polypeptide; or (d) the non-native transmembrane domain is derived from NKG2D, the non-native stimulatory domain is derived from 2B4, and the non-native signaling domain is derived from CD3ζ. 46. The method of claim 43, wherein the first CAR and the second CAR are the same or are different in targeting specificity, and the first CAR or the second CAR is: (i) T cell specific or NK cell specific; (ii) a bi-specific antigen binding CAR; (iii) a switchable CAR; (iv) a dimerized CAR; (v) a split CAR; (vi) a multi-chain CAR; (vii) an inducible CAR; (viii) co-expressed with another CAR; (ix) co-expressed with a partial or full length peptide of a cell surface expressed exogenous cytokine and/or a receptor thereof, optionally in separate constructs or in a bi- cistronic construct; (x) co-expressed with a checkpoint inhibitor, optionally in separate constructs or in a bi-cistronic construct; (xi) specific to CD19 or BCMA; and/or (xii) specific to any one of ADGRE2, carbonic anhydrase IX (CAIX), CCR1, CCR4, carcinoembryonic antigen (CEA), CD3, CD5, CD7, CD8, CD10, CD20, CD22, CD30, CD33, CD34, CD38, CD41, CD44, CD44V6, CD49f, CD56, CD70, CD74, CD99, CD123, CD133, CD138, CDS, CLEC12A, an antigen of a cytomegalovirus (CMV) infected cell, epithelial glycoprotein2 (EGP-2), epithelial glycoprotein-40 (EGP-40), epithelial cell adhesion molecule (EpCAM), EGFRvIII, receptor tyrosine-protein kinases erb-B2,3,4, EGFIR, EGFR-VIII, ERBB folate-binding protein (FBP), fetal acetylcholine receptor (AChR), folate receptor-a, Ganglioside G2 (GD2), Ganglioside G3 (GD3), human Epidermal Growth Factor Receptor 2 (HER-2), human telomerase reverse transcriptase (hTERT), ICAM-1, Integrin B7, Interleukin-13 receptor subunit alpha-2 (IL-13Rα2), κ-light chain, kinase insert domain receptor (KDR), Lewis A (CA19.9), Lewis Y (LeY), L1 cell adhesion molecule (L1-CAM), LILRB2, melanoma antigen family A 1 (MAGE-A1), MICA/B, Mucin 1 (Muc-1), Mucin 16 (Muc-16), Mesothelin (MSLN), NKCSI, NKG2D ligands, c-Met, cancer-testis antigen NY-ESO-1, oncofetal antigen (h5T4), PRAME, prostate stem cell antigen (PSCA), PRAME prostate-specific membrane antigen (PSMA), tumor- associated glycoprotein 72 (TAG-72), TIM-3, TRBC1, TRBC2, vascular endothelial growth factor R2 (VEGF- R2), Wilms tumor protein (WT-1), and a pathogen antigen. 47. The method of claim 43, wherein the partial or full length peptide of a cell surface expressed exogenous cytokine and/or a receptor thereof: (a) comprises at least one of IL2, IL4, IL6, IL7, IL9, IL10, IL11, IL12, IL15, IL18, IL21, and/or respective receptors thereof; or (b) comprises at least one of: (i) co-expression of IL15 and IL15Rα by using a self-cleaving peptide; (ii) a fusion protein of IL15 and IL15Rα; (iii) an IL15/IL15Rα fusion protein with intracellular domain of IL15Rα truncated; (iv) a fusion protein of IL15 and membrane bound Sushi domain of IL15Rα; (v) a fusion protein of IL15 and IL15Rβ; (vi) a fusion protein of IL15 and common receptor γC, wherein the common receptor γC is native or modified; and (vii) a homodimer of IL15Rβ; wherein any one of (i)-(vii) can be co-expressed with a CAR in separate constructs or in a bi-cistronic construct; and optionally, (c) is transiently expressed. 48. The method of claim 43, wherein the first genetically engineered iPSC or the second genetically engineered iPSC further comprises one or more of: (i) HLA-I deficiency; (ii) HLA-II deficiency; (iii) introduced expression of HLA-G or non-cleavable HLA-G; (iv) at least one of lig-, inR+, cs-CD3+, En+, and Ab+; wherein (1) lig- is negative in an expressed alloantigen; (2) inR+ is positive in an expressed inactivation-CAR corresponding to the negative alloantigen; (3) cs-CD3+ is positive in cell surface expressed CD3; (4) En+ is positive in at least one expressed engager, wherein the engager comprises a bi-specific T cell engager (BiTE), or a tri-specific killer cell engager (TriKE); and (5) Ab+ is positive in at least one expressed antibody or checkpoint inhibitor; (v) deletion or reduced expression in at least one of B2M, CIITA, TAP1, TAP2, Tapasin, NLRC5, PD1, LAG3, TIM3, RFXANK, RFX5, RAG1, RFXAP, and any gene in the chromosome 6p21 region; and (vi) introduced or increased expression in at least one of HLA-E, HLA-G, 41BBL, CD4, CD8, CD16, CD47, CD113, CD131, CD137, CD80, PDL1, A2AR, TCR, Fc receptor, and surface triggering receptor for coupling with bi- or multi- specific or universal engagers. 49. The method of claim 48, wherein (i) the alloantigen comprises CD40L, OX40, or 4-1BB; (ii) the inactivation-CAR comprises CD40L-CAR, OX40-CAR, or 4-1BB-CAR; (iii) the BiTE or the TriKE is specific to (a) an immune cell surface molecule comprising CD3, CD28, CD5, CD16, NKG2D, CD64, CD32, CD89, NKG2C, or a chimeric Fc receptor thereof; and (b) a tumor surface molecule comprising B7H3, BCMA, CD10, CD19, CD20, CD22, CD24, CD30, CD33, CD34, CD38, CD44, CD79a, CD79b, CD123, CD138, CD179b, CEA, CLEC12A, CS-1, DLL3, EGFR, EGFRvIII, EPCAM, FLT-3, FOLR1, FOLR3, GD2, gpA33, HER2, HM1.24, LGR5, MSLN, MCSP, MICA/B, PSMA, PAMA, P-cadherin, or ROR1; (iv) the BiTE comprises CD3-CD19, CD16-CD30, CD64-CD30, CD16-BCMA, CD64- BCMA, or CD3-CD33; (v) the TriKE comprises CD16-IL15-EPCAM, CD64-IL15-EPCAM, CD16-IL15-CD33, CD64-IL15-CD33, or NKG2C-IL15-CD33; (vi) the antibody comprises an anti-CD20, anti-HER2, anti-CD52, anti-EGFR, anti- CD123, anti-GD2, anti-PDL1, or anti-CD38 antibody; or (vii) the checkpoint inhibitor comprises (a) an antagonist to a checkpoint molecule comprising PD-1, PDL-1, TIM-3, TIGIT, LAG-3, CTLA-4, 2B4, 4-1BB, 4-1BBL, A2AR, BATE, BTLA, CD39, CD47, CD73, CD94, CD96, CD160, CD200, CD200R, CD274, CEACAM1, CSF-1R, Foxpl, GARP, HVEM, IDO, EDO, TDO, LAIR-1, MICA/B, NR4A2, MAFB, OCT-2, Rara (retinoic acid receptor alpha), TLR3, VISTA, NKG2A/HLA-E, or inhibitory KIR; (b) one of atezolizumab, avelumab, durvalumab, ipilimumab, IPH4102, IPH43, IPH33, lirimumab, monalizumab, nivolumab, pembrolizumab, and their derivatives or functional equivalents; or (c) one of atezolizumab, nivolumab, and pembrolizumab. 50. The method of claim 43, wherein the first genetically engineered iPSC or the second genetically engineered iPSC comprise: (i) one or more exogenous polynucleotides integrated in one desired integration site; or (ii) more than two exogenous polynucleotides integrated in different desired integration sites. 51. The method of claim 50, wherein the desired integration site comprises at least one of AAVS1, CCR5, ROSA26, collagen, HTRP, H11, GAPDH, RUNX1, B2M, TAP1, TAP2, tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR α or β constant region, NKG2A, NKG2D, CD25, CD38, CD40L, CD44, CD54, CD56, CD58, CD69, CD71, OX40, 4-1BB, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, and TIGIT. 52. The method of claim 50, wherein the desired integration site comprises TCR α or β constant region, CD25, CD38, CD40L, CD44, CD54, CD58, CD69, CD71, OX40 or 4-1BB; and optionally, wherein the TCRα or TCRβ, CD25, CD38, CD40L, CD44, CD54, CD58, CD69, CD71, OX40 or 4-1BB is knocked out as a result of integrating said one or more exogenous polynucleotides at the respective integration site. 53. The method of claim 43, wherein the iPSC-derived NK cells or the iPSC-derived T cells have at least one of the following characteristics comprising: (i) improved persistency and/or survival, (ii) increased resistance to native immune cells, (iii) increased cytotoxicity, (iv) improved tumor penetration, (v) enhanced or acquired ADCC, (vi) enhanced ability in migrating, and/or activating or recruiting bystander immune cells to tumor sites; (vii) enhanced ability to reduce tumor immunosuppression, and (viii) improved ability in rescuing tumor antigen escape, in comparison to its native counterpart cell obtained from peripheral blood, umbilical cord blood, or any other donor tissues. 54. The method of claim 43, wherein the first synthetic cell population or the second synthetic cell population is modulated ex vivo. 55. The method of claim 54, wherein the modulated first synthetic cell population comprising iPSC-derived NK cells comprises an increased number or ratio of type I NKT cells, and/or adaptive NK cells, as compared to the first synthetic cell population without being modulated; or wherein the second modulated synthetic cell population comprising iPSC- derived T cells comprises an increased number or ratio of naïve T cells, stem cell memory T cells, and/or central memory T cells, as compared to the second synthetic cell population without being modulated. 56. The method of claim 43, wherein: (i) the iPSC-derived NK cells and the iPSC-derived T cells are in a ratio ranging from 100:1 to 1:100; (ii) the method further comprises adding one or more additional cell populations to the produced first and second synthetic cell populations; or (iii) the method further comprises adding one or more therapeutic agents to the produced first and second synthetic cell populations. 57. The method of claim 56, wherein the one or more additional cell populations comprise regulatory cells. 58. The method of claim 57, wherein the regulatory cells are iPSC-derived immune regulatory cells or myeloid derived suppressor cells (MDSCs). 59. The method of claim 56, wherein the one or more therapeutic agents comprise a peptide, a cytokine, a checkpoint inhibitor, a mitogen, a growth factor, a small RNA, a dsRNA (double stranded RNA), mononuclear blood cells, feeder cells, feeder cell components or replacement factors thereof, a vector comprising one or more polynucleic acids of interest, an antibody, a chemotherapeutic agent or a radioactive moiety, or an immunomodulatory drug (IMiD). 60. The method of claim 59, wherein the checkpoint inhibitor comprises: (a) one or more antagonist checkpoint molecules comprising PD-1, PDL-1, TIM-3, TIGIT, LAG-3, CTLA-4, 2B4, 4-1BB, 4-1BBL, A2AR, BATE, BTLA, CD39, CD47, CD73, CD94, CD96, CD160, CD200, CD200R, CD274, CEACAM1, CSF-1R, Foxpl, GARP, HVEM, IDO, EDO, TDO, LAIR-1, MICA/B, NR4A2, MAFB, OCT-2, Rara (retinoic acid receptor alpha), TLR3, VISTA, NKG2A/HLA-E, or inhibitory KIR; (b) one or more of atezolizumab, avelumab, durvalumab, ipilimumab, IPH4102, IPH43, IPH33, lirimumab, monalizumab, nivolumab, pembrolizumab, and their derivatives or functional equivalents; or (c) at least one of atezolizumab, nivolumab, and pembrolizumab. 61. The method of claim 59, wherein the antibody comprises: (a) anti-CD20, anti-HER2, anti-CD52, anti-EGFR, anti-CD123, anti-GD2, anti-PDL1, and/or anti-CD38 antibody; (b) one or more of retuximab, veltuzumab, ofatumumab, ublituximab, ocaratuzumab, obinutuzumab, trastuzumab, pertuzumab, alemtuzumab, certuximab, dinutuximab, avelumab, daratumumab, isatuximab, MOR202, 7G3, CSL362, elotuzumab, and their humanized or Fc modified variants or fragments and their functional equivalents and biosimilars; or (c) daratumumab. 62. The method of claim 43, further comprising combining the first synthetic cell population and the second synthetic cell population into a mixed population. |
[000179] As such, one aspect of the present application provides a composition comprising two or more synthetic effector cell types that have been differentiated from genomically engineered iPSCs. Thus, in various embodiments, the composition comprises a first population of synthetic effector cells that have been differentiated from genomically engineered iPSCs, and a second population of synthetic effector cells that have been differentiated from genomically engineered iPSCs. In one embodiment of the composition, the first type of synthetic effector cell or population thereof (i.e., first population) is a functionally enhanced iPSC-derived T cell, and the second type of synthetic effector cell or population thereof (i.e., second population) is a functionally enhanced iPSC-derived NK cell. In some embodiments, the functionally enhanced iPSC-derived T cell comprises at least a (first) CAR. In some embodiments, the functionally enhanced iPSC-derived NK cell comprises at least a (second) CAR, and one or both of a CD16 variant and a partial or full length of a cell surface expressed exogenous cytokine and/or a receptor thereof. In various embodiments, the CD16 variant is a high affinity non-cleavable CD16 (hnCD16). [000180] As provided, the embodiments of said high affinity non-cleavable CD16 (hnCD16) or a variant thereof comprise at least one of the following: (a) F176V and S197P in ectodomain domain of CD16; (b) a full or partial ectodomain originated from CD64; (c) a non- native (or non-CD16) transmembrane domain; (d) a non-native (or non-CD16) intracellular domain; (e) a non-native (or non-CD16) signaling domain; (f) a non-native stimulatory domain; and (g) transmembrane, signaling, and stimulatory domains that are not originated from CD16, and are originated from the same or different polypeptides. In some embodiments, the non- native transmembrane domain is derived from CD3D, CD3E, CD3G, CD3ζ, CD4, CD8, CD8a, CD8b, CD27, CD28, CD40, CD84, CD166, 4-1BB, OX40, ICOS, ICAM-1, CTLA-4, PD-1, LAG-3, 2B4, BTLA, CD16, IL7, IL12, IL15, KIR2DL4, KIR2DS1, NKp30, NKp44, NKp46, NKG2C, NKG2D, or T cell receptor (TCR) polypeptide. In some embodiments, the non-native stimulatory domain is derived from CD27, CD28, 4-1BB, OX40, ICOS, PD-1, LAG-3, 2B4, BTLA, DAP10, DAP12, CTLA-4, or NKG2D polypeptide. In some other embodiments, the non-native signaling domain is derived from CD3ζ, 2B4, DAP10, DAP12, DNAM1, CD137 (4- 1BB), IL21, IL7, IL12, IL15, NKp30, NKp44, NKp46, NKG2C, or NKG2D polypeptide. In yet some other embodiments, the non-native transmembrane domain is derived from NKG2D, the non-native stimulatory domain is derived from 2B4, and the non-native signaling domain is derived from CD3ζ. [000181] As provided, the first CAR of the synthetic cells in the first population and the second CAR of the synthetic cells in the second population provide targeting specificity to the synthetic cells. In some embodiments, the first CAR and the second CAR have the same targeting specificity. In some embodiments, the first CAR and the second CAR are different in targeting specificity. In some embodiments, the first CAR and the second CAR are the same or are different in targeting specificity, and the first CAR and/or the second CAR may have any one of the following characteristics, such that the first and/or the second CAR is: (i) T cell specific; (ii) NK cell specific; (iii) a bi-specific antigen binding CAR; (iv) a switchable CAR; (v) a dimerized CAR; (vi) a split CAR; (vii) a multi-chain CAR; or (viii) an inducible CAR. In some other embodiments, the first and/or the second CAR is co-expressed with yet another CAR, which may have the same or different targeting specificity as either of the first or second CAR. [000182] In some embodiments, the first and/or the second CAR is co-expressed with a partial or full length peptide of a cell surface expressed exogenous cytokine and/or a receptor thereof, optionally in separate constructs or in a bi-cistronic construct. In yet some other embodiments, the first and/or the second CAR is co-expressed with a checkpoint inhibitor, optionally in separate constructs or in a bi-cistronic construct. In some embodiments, the first and/or the second CAR is specific to CD19 or BCMA. In other embodiments, the first and/or the second CAR is specific to at least one of ADGRE2, carbonic anhydrase IX (CAIX), CCR1, CCR4, carcinoembryonic antigen (CEA), CD3, CD5, CD7, CD8, CD10, CD20, CD22, CD30, CD33, CD34, CD38, CD41, CD44, CD44V6, CD49f, CD56, CD70, CD74, CD99, CD123, CD133, CD138, CDS, CLEC12A, an antigen of a cytomegalovirus (CMV) infected cell, epithelial glycoprotein2 (EGP-2), epithelial glycoprotein-40 (EGP-40), epithelial cell adhesion molecule (EpCAM), EGFRvIII, receptor tyrosine-protein kinases erb-B2,3,4, EGFIR, EGFR- VIII, ERBB folate-binding protein (FBP), fetal acetylcholine receptor (AChR), folate receptor-a, Ganglioside G2 (GD2), Ganglioside G3 (GD3), human Epidermal Growth Factor Receptor 2 (HER-2), human telomerase reverse transcriptase (hTERT), ICAM-1, Integrin B7, Interleukin- 13 receptor subunit alpha-2 (IL-13Rα2), κ-light chain, kinase insert domain receptor (KDR), Lewis A (CA19.9), Lewis Y (LeY), L1 cell adhesion molecule (L1-CAM), LILRB2, melanoma antigen family A 1 (MAGE-A1), MICA/B, Mucin 1 (Muc-1), Mucin 16 (Muc-16), Mesothelin (MSLN), NKCSI, NKG2D ligands, c-Met, cancer-testis antigen NY-ESO-1, oncofetal antigen (h5T4), PRAME, prostate stem cell antigen (PSCA), PRAME prostate-specific membrane antigen (PSMA), tumor-associated glycoprotein 72 (TAG-72), TIM-3, TRBC1, TRBC2, vascular endothelial growth factor R2 (VEGF-R2), Wilms tumor protein (WT-1), and a pathogen antigen. [000183] In some embodiments of the CAR-expressing cells of the first or the second population, the cells also express a partial or full length peptide of an exogenous cell surface cytokine and/or a receptor thereof. In some embodiments, the exogenous cell surface cytokine and/or a receptor variant thereof comprises at least one of IL2, IL4, IL6, IL7, IL9, IL10, IL11, IL12, IL15, IL18, IL21, and/or respective receptor thereof. In some other embodiments, the cytokine and/or a receptor variant thereof comprises at least one of: (i) co-expression of IL15 and IL15Rα by using a self-cleaving peptide; (ii) a fusion protein of IL15 and IL15Rα; (iii) an IL15/IL15Rα fusion protein with intracellular domain of IL15Rα truncated; (iv) a fusion protein of IL15 and membrane bound Sushi domain of IL15Rα; (v) a fusion protein of IL15 and IL15Rβ; (vi) a fusion protein of IL15 and common receptor γC, wherein the common receptor γC is native or modified; and (vii) a homodimer of IL15Rβ, and any one of (i)-(vii) can be co- expressed with a CAR in separate constructs or in a bi-cistronic construct. In some embodiments, the partial or full length peptide of a cell surface exogenous cytokine and/or a receptor thereof is transiently expressed in the cell. [000184] In some embodiments, the genetically modified iPSC and the functionally enhanced derivative effective cells therefrom, which include, but are not limited to iPSC-derived T and NK cells, comprise: (i) HLA-I deficiency, or B2M null or low; (ii) HLA-II deficiency, or CIITA null or low; (iii) introduced expression of HLA-G or non-cleavable HLA-G; (iv) at least one of lig-, inR + , cs-CD3 + , En + , and Ab + ; wherein “lig-” is negative in an expressed alloantigen; “inR + ” is positive in an expressed inactivation-CAR corresponding to the negative alloantigen; “cs-CD3 + ” is positive in cell surface expressed CD3; “En + ” is positive in at least one expressed engager, wherein the engager comprises a bi-specific T cell engager (BiTE), or a tri-specific killer cell engager (TriKE); and “Ab + ” is positive in at least one expressed antibody or checkpoint inhibitor; (v) one or more of deletion or reduced expression of TAP1, TAP2, Tapasin, NLRC5, PD1, LAG3, TIM3, RFXANK, RFX5, RFXAP, RAG1, and any gene in the chromosome 6p21 region; and (vi) introduced or increased expression of at least one of HLA-E, HLA-G, 4-1BBL, CD4, CD8, CD16, CD47, CD113, CD131, CD137, CD80, PDL1, A2AR, TCR, Fc receptor, and surface triggering receptor for coupling with bi-, multi- specific or universal engagers. [000185] In some embodiments, said alloantigen to be knocked-out or knocked down in the iPSC-derived effector cells, including the derivative NK or T cells, comprises CD40L, OX40, or 4-1BB, which are up-regulated in activated recipient T, NK or B cells. In some embodiments, said inactivation-CAR in the iPSC-derived effector cells comprises CD40L-CAR, OX40-CAR, or 4-1BB-CAR, corresponding to the knocked-out alloantigen molecule in the iPSC-derived effector cells. [000186] In some embodiments, the BiTE or TriKE expressed in the iPSC-derived effector cells recognize at least one immune cell surface molecule comprising CD3, CD28, CD5, CD16, NKG2D, CD64, CD32, CD89, NKG2C, or a chimeric Fc receptor thereof, and at least one tumor surface molecule comprising B7H3, BCMA, CD10, CD19, CD20, CD22, CD24, CD30, CD33, CD34, CD38, CD44, CD79a, CD79b, CD123, CD138, CD179b, CEA, CLEC12A, CS-1, DLL3, EGFR, EGFRvIII, EPCAM, FLT-3, FOLR1, FOLR3, GD2, gpA33, HER2, HM1.24, LGR5, MSLN, MCSP, MICA/B, PSMA, PAMA, P-cadherin, or ROR1. In some embodiments, the BiTE expressed in the iPSC-derived effector cells comprises CD3-CD19, CD16-CD30, CD64-CD30, CD16-BCMA, CD64-BCMA, or CD3-CD33. In some embodiments, the TriKE expressed in the iPSC-derived effector cells comprises CD16-IL15-EPCAM, CD64-IL15- EPCAM, CD16-IL15-CD33, CD64-IL15-CD33, or NKG2C-IL15-CD33. [000187] In some embodiments of the iPSC-derived effector cells, the cells express an antibody, wherein the antibody includes, but is not limited to an anti-CD20, anti-HER2, anti- CD52, anti-EGFR, anti-CD123, anti-GD2, anti-PDL1, antibody, or an anti-CD38 antibody. In some embodiments of the iPSC-derived effector cells, the cells express a checkpoint inhibitor, which includes, but is not limited to, an antagonist to a checkpoint molecule comprising PD-1, PDL-1, TIM-3, TIGIT, LAG-3, CTLA-4, 2B4, 4-1BB, 4-1BBL, A 2A R, BATE, BTLA, CD39, CD47, CD73, CD94, CD96, CD160, CD200, CD200R, CD274, CEACAM1, CSF-1R, Foxpl, GARP, HVEM, IDO, EDO, TDO, LAIR-1, MICA/B, NR4A2, MAFB, OCT-2, Rara (retinoic acid receptor alpha), TLR3, VISTA, NKG2A/HLA-E, or inhibitory KIR. In some embodiments, the expressed checkpoint inhibitor in the iPSC-derived effector cells is one of atezolizumab, avelumab, durvalumab, ipilimumab, IPH4102, IPH43, IPH33, lirimumab, monalizumab, nivolumab, pembrolizumab, or a derivative or functional equivalent thereof. In yet another embodiment, the checkpoint inhibitor expressed in the iPSC-derived effector cells is one of atezolizumab, nivolumab, and pembrolizumab. [000188] As provided herein, the synthetic cells including, but not limited to iPSC-derived T cells or the iPSC-derived NK cells, of the first and the second cell populations of the composition each comprise one or more exogenous polynucleotides that contribute to the unique features of the synthetic cells. In some embodiments, the iPSC-derived T cells and/or the iPSC- derived NK cells comprise one or more exogenous polynucleotides integrated in one desired integration site. In some other embodiments, the iPSC-derived T cells and/or the iPSC-derived NK cells comprise more than two exogenous polynucleotides integrated in different desired integration sites. In some embodiments, the desired integration site(s) comprises at least one of AAVS1, CCR5, ROSA26, collagen, HTRP, H11, GAPDH, RUNX1, B2M, TAP1, TAP2, tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR α or β constant region (TRAC or TRBC), NKG2A, NKG2D, CD25, CD38, CD40L, CD44, CD54, CD56, CD58, CD69, CD71, OX40, 4- 1BB, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, and TIGIT. In some other embodiments, the desired integration site(s) comprises TCR α or β constant region (TRAC or TRBC), CD25, CD38, CD40L, CD44, CD54, CD58, CD69, CD71, OX40 or 4-1BB. In yet some other embodiments, TCRα or TCRβ, CD25, CD38, CD40L, CD44, CD54, CD58, CD69, CD71, OX40 or 4-1BB is knocked-out as a result of integrating said one or more exogenous polynucleotides at the respective integration site(s). [000189] In the embodiments of the composition comprising two or more synthetic cell populations, the synthetic cells of each population are derived from genomically engineered iPSC. In various embodiments, the first population is a population of iPSC-derived T cells and the second population is a population of iPSC-derived NK cells, or vice versa (i.e., the first population is a population of iPSC-derived NK cells and the second population is a population of iPSC-derived T cells). In some embodiments, the first population of iPSC-derived T cells and the second population of iPSC-derived NK cells each have at least one of the following characteristics: (i) improved persistency and/or survival, (ii) increased resistance to native immune cells, (iii) increased cytotoxicity, (iv) improved tumor penetration, (v) enhanced or acquired ADCC, (vi) enhanced ability in migrating, and/or activating or recruiting bystander immune cells to tumor sites; (vii) enhanced ability to reduce tumor immunosuppression, and (viii) improved ability in rescuing tumor antigen escape, in comparison to their native counterpart cells obtained from peripheral blood, umbilical cord blood, or any other donor tissues. In addition, the iPSC-derived T cells and/or the iPSC-derived NK cells comprise longer telomeres in comparison to their respective native counterpart cells obtained from peripheral blood, umbilical cord blood, or any other donor tissues. [000190] In some embodiments of the composition comprising two or more synthetic cell populations, the synthetic cells of the first and/or the second population that are derived from genomically engineered iPSC are modulated. In some embodiments, the modulated synthetic cells of the first population are iPSC-derived T cells, and the first population comprises an increased number or ratio of naïve T cells, stem cell memory T cells, and/or central memory T cells in comparison to the first cell population without modulation. In some embodiments, the modulated synthetic cells of the second population are iPSC-derived NK cells, and the second cell population comprises an increased number or ratio of type I NKT cells, and/or adaptive NK cells in comparison to the cell population without modulation. [000191] In some embodiments of the composition comprising a first synthetic cell population comprising derivative T cells differentiated from engineered iPSC, and a second synthetic cell population comprising derivative NK cells differentiated from engineered iPSC, the derivative T cells and the derivative NK cells are in a ratio ranging from 100:1 to 1:100. In some embodiments, the derivative T cells and the derivative NK cells are in a ratio ranging from 50:1 to 1:50. In some embodiments, the derivative T cells and the derivative NK cells are in a ratio ranging from 20:1 to 1:20. In some other embodiments, the derivative T cells and the derivative NK cells are in a ratio ranging from 10:1 to 1:10. In yet some other embodiments, the derivative T cells and the derivative NK cells are in a ratio of 1:1. [000192] In some embodiments of the composition comprising a first synthetic cell population comprising derivative T cells differentiated from engineered iPSC, and a second synthetic cell population comprising derivative NK cells differentiated from engineered iPSC, the composition further comprises one or more additional cell populations. In one embodiment, the additional cell population comprises regulatory cells. In another embodiment, the additional cell population comprises myeloid derived suppressor cells (MDSCs). In yet another embodiment, the MDSCs of the additional cell population are derived from iPSC. [000193] Yet another aspect of this application provides a composition as described above that further comprises one or more therapeutic agents in addition to at least two synthetic cell populations comprising iPSC-derived T cells and iPSC-derived NK cells, respectively. Suitable therapeutic agents, including, but not limited to, antibodies and checkpoint inhibitors that can be used with the synthetic cells are further detailed below. II. Methods for Targeted Genome Editing at Selected Locus in iPSCs [000194] Genome editing, or genomic editing, or genetic editing, as used interchangeably herein, is a type of genetic engineering in which DNA is inserted, deleted, and/or replaced in the genome of a targeted cell. Targeted genome editing (interchangeable with “targeted genomic editing” or “targeted genetic editing”) enables insertion, deletion, and/or substitution at pre- selected sites in the genome. When an endogenous sequence is deleted at the insertion site during targeted editing, an endogenous gene comprising the affected sequence may be knocked- out or knocked-down due to the sequence deletion. Therefore, targeted editing may also be used to disrupt endogenous gene expression with precision. Similarly used herein is the term “targeted integration,” referring to a process involving insertion of one or more exogenous sequences, with or without deletion of an endogenous sequence at the insertion site. In comparison, randomly integrated genes are subject to position effects and silencing, making their expression unreliable and unpredictable. For example, centromeres and sub-telomeric regions are particularly prone to transgene silencing. Reciprocally, newly integrated genes may affect the surrounding endogenous genes and chromatin, potentially altering cell behavior or favoring cellular transformation. Therefore, inserting exogenous DNA in a pre-selected locus such as a safe harbor locus, or genomic safe harbor (GSH) is important for safety, efficiency, copy number control, and for reliable gene response control. [000195] Targeted editing can be achieved either through a nuclease-independent approach, or through a nuclease-dependent approach. In the nuclease-independent targeted editing approach, homologous recombination is guided by homologous sequences flanking an exogenous polynucleotide to be inserted, through the enzymatic machinery of the host cell. [000196] Alternatively, targeted editing could be achieved with higher frequency through specific introduction of double strand breaks (DSBs) by specific rare-cutting endonucleases. Such nuclease-dependent targeted editing utilizes DNA repair mechanisms including non-homologous end joining (NHEJ), which occurs in response to DSBs. Without a donor vector containing exogenous genetic material, the NHEJ often leads to random insertions or deletions (in/dels) of a small number of endogenous nucleotides. In comparison, when a donor vector containing exogenous genetic material flanked by a pair of homology arms is present, the exogenous genetic material can be introduced into the genome during homology directed repair (HDR) by homologous recombination, resulting in a “targeted integration.” In some situations, the targeted integration site is intended to be within a coding region of a selected gene, and thus the targeted integration could disrupt the gene expression, resulting in simultaneous knock-in and knock-out (KI/KO) in one single editing step. [000197] Inserting one or more transgenes at a selected position in a gene locus of interest (GOI) to knock-out the gene at the same time can be achieved. Gene loci suitable for simultaneous knock-in and knock-out (KI/KO) include, but are not limited to, B2M, TAP1, TAP2, tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR α or β constant region (TRAC or TRBC), NKG2A, NKG2D, CD25, CD38, CD44, CD54, CD56, CD58, CD69, CD71, OX40, 4-1BB, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, and TIGIT. With respective site- specific targeting homology arms for position-selective insertion, it allows the transgene(s) to express either under an endogenous promoter at the site or under an exogenous promoter comprised in the construct. When two or more transgenes are to be inserted at a selected location (e.g., in a CD38 locus), a linker sequence, for example, a 2A linker or IRES, is placed between any two transgenes. The 2A linker encodes a self-cleaving peptide derived from FMDV, ERAV, PTV-I, or TaV (referred to as “F2A”, “E2A”, “P2A”, and “T2A”, respectively), allowing for separate proteins to be produced from a single translation. In some embodiments, insulators are included in the construct to reduce the risk of transgene and/or exogenous promoter silencing. In various embodiments, the exogenous promoter may be CAG, or other constitutive, inducible, temporal-, tissue-, or cell type- specific promoters including, but not limited to CMV, EF1α, PGK, and UBC. [000198] Available endonucleases capable of introducing specific and targeted DSBs include, but are not limited to, zinc-finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN), RNA-guided CRISPR (Clustered Regular Interspaced Short Palindromic Repeats) systems. Additionally, the DICE (dual integrase cassette exchange) system utilizing phiC31 and Bxb1 integrases is also a promising tool for targeted integration. [000199] ZFNs are targeted nucleases comprising a nuclease fused to a zinc finger DNA binding domain. By a “zinc finger DNA binding domain” or “ZFBD”, it is meant a polypeptide domain that binds DNA in a sequence-specific manner through one or more zinc fingers. A zinc finger is a domain of about 30 amino acids within the zinc finger binding domain whose structure is stabilized through coordination of a zinc ion. Examples of zinc fingers include, but are not limited to, C 2 H 2 zinc fingers, C 3 H zinc fingers, and C 4 zinc fingers. A “designed” zinc finger domain is a domain not occurring in nature whose design/composition results principally from rational criteria, e.g., application of substitution rules and computerized algorithms for processing information in a database storing information of existing ZFP designs and binding data. See, for example, U.S. Pat. Nos.6,140,081; 6,453,242; and 6,534,261; see also WO98/53058; WO98/53059; WO98/53060; WO02/016536 and WO03/016496, the complete disclosures of which are incorporated herein by reference. A “selected” zinc finger domain is a domain not found in nature whose production results primarily from an empirical process such as phage display, interaction trap or hybrid selection. ZFNs are described in greater detail in U.S. Pat. No.7,888,121 and U.S. Pat. No.7,972,854, the complete disclosures of which are incorporated herein by reference. The most recognized example of a ZFN in the art is a fusion of the FokI nuclease with a zinc finger DNA binding domain. [000200] A TALEN is a targeted nuclease comprising a nuclease fused to a TAL effector DNA binding domain. By “transcription activator-like effector DNA binding domain”, “TAL effector DNA binding domain”, or “TALE DNA binding domain”, it is meant the polypeptide domain of TAL effector proteins that is responsible for binding of the TAL effector protein to DNA. TAL effector proteins are secreted by plant pathogens of the genus Xanthomonas during infection. These proteins enter the nucleus of the plant cell, bind effector-specific DNA sequences via their DNA binding domain, and activate gene transcription at these sequences via their transactivation domains. TAL effector DNA binding domain specificity depends on an effector-variable number of imperfect 34 amino acid repeats, which comprise polymorphisms at select repeat positions called repeat variable-diresidues (RVD). TALENs are described in greater detail in US Patent Application No.2011/0145940, which is herein incorporated by reference. The most recognized example of a TALEN in the art is a fusion polypeptide of the FokI nuclease to a TAL effector DNA binding domain. [000201] Another example of a targeted nuclease that finds use in the subject methods is a targeted Spo11 nuclease, a polypeptide comprising a Spo11 polypeptide having nuclease activity fused to a DNA binding domain, e.g. a zinc finger DNA binding domain, a TAL effector DNA binding domain, etc. that has specificity for a DNA sequence of interest. [000202] Additional examples of targeted nucleases suitable for the present invention include, but not limited to Bxb1, phiC31, R4, PhiBT1, and Wβ/SPBc/TP901-1, whether used individually or in combination. [000203] Other non-limiting examples of targeted nucleases include naturally occurring and recombinant nucleases; CRISPR related nucleases from families including cas, cpf, cse, csy, csn, csd, cst, csh, csa, csm, and cmr; restriction endonucleases; meganucleases; homing endonucleases, and the like. [000204] Using Cas9 as an example, CRISPR/Cas9 typically requires two major components: (1) a Cas9 endonuclease and (2) the crRNA-tracrRNA complex. When co- expressed, the two components form a complex that is recruited to a target DNA sequence comprising PAM and a seeding region near PAM. The crRNA and tracrRNA can be combined to form a chimeric guide RNA (gRNA) to guide Cas9 to target selected sequences. These two components can then be delivered to mammalian cells via transfection or transduction. Use of the CRISPR/Cpf system, typically requires (1) a Cpf endonuclease (e.g., Cpf1, MAD7 and many more known in the art) and (2) the gNA, which often does not need tracrRNA, to guide Cpf endonuclease to target selected sequences. [000205] DICE mediated insertion uses a pair of recombinases, for example, phiC31 and Bxb1, to provide unidirectional integration of an exogenous DNA that is tightly restricted to each enzymes’ own small attB and attP recognition sites. Because these target att sites are not naturally present in mammalian genomes, they must be first introduced into the genome, at the desired integration site. See, for example, U.S. Pub. No.2015/0140665, the disclosure of which is incorporated herein by reference. [000206] One aspect of the present invention provides a construct comprising one or more exogenous polynucleotides for targeted genome integration. Thus, the synthetic cells of the first and second populations of the composition of the invention may be produced using one or more constructs comprising one or more exogenous polynucleotides for targeted genome integration. In one embodiment, the construct further comprises a pair of homologous arms specific to a desired integration site, and the method of targeted integration comprises introducing the construct to cells to enable site specific homologous recombination by the cell host enzymatic machinery. In another embodiment, the method of targeted integration in a cell comprises introducing a construct comprising one or more exogenous polynucleotides to the cell, and introducing a ZFN expression cassette comprising a DNA-binding domain specific to a desired integration site to the cell to enable a ZFN-mediated insertion. In yet another embodiment, the method of targeted integration in a cell comprises introducing a construct comprising one or more exogenous polynucleotides to the cell, and introducing a TALEN expression cassette comprising a DNA-binding domain specific to a desired integration site to the cell to enable a TALEN-mediated insertion. In another embodiment, the method of targeted integration in a cell comprises introducing a construct comprising one or more exogenous polynucleotides to the cell, introducing a Cas9 expression cassette, and a gRNA comprising a guide sequence specific to a desired integration site to the cell to enable a Cas9-mediated insertion. In still another embodiment, the method of targeted integration in a cell comprises introducing a construct comprising one or more att sites of a pair of DICE recombinases to a desired integration site in the cell, introducing a construct comprising one or more exogenous polynucleotides to the cell, and introducing an expression cassette for DICE recombinases, to enable DICE-mediated targeted integration. [000207] Promising sites for targeted integration include, but are not limited to, safe harbor loci, or genomic safe harbor (GSH), which are intragenic or extragenic regions of the human genome that, theoretically, are able to accommodate predictable expression of newly integrated DNA without adverse effects on the host cell or organism. A useful safe harbor must permit sufficient transgene expression to yield desired levels of the vector-encoded protein or non- coding RNA. A safe harbor also must not predispose cells to malignant transformation nor alter cellular functions. For an integration site to be a potential safe harbor locus, it ideally needs to meet criteria including, but not limited to: absence of disruption of regulatory elements or genes, as judged by sequence annotation; is an intergenic region in a gene dense area, or a location at the convergence between two genes transcribed in opposite directions; keep distance to minimize the possibility of long-range interactions between vector-encoded transcriptional activators and the promoters of adjacent genes, particularly cancer-related and microRNA genes; and has apparently ubiquitous transcriptional activity, as reflected by broad spatial and temporal expressed sequence tag (EST) expression patterns, indicating ubiquitous transcriptional activity. This latter feature is especially important in stem cells, where during differentiation, chromatin remodeling typically leads to silencing of some loci and potential activation of others. Within the region suitable for exogenous insertion, a precise locus chosen for insertion should be devoid of repetitive elements and conserved sequences and to which primers for amplification of homology arms could easily be designed. [000208] Suitable sites for human genome editing, or specifically, targeted integration, include, but are not limited to the adeno-associated virus site 1 (AAVS1), the chemokine (CC motif) receptor 5 (CCR5) gene locus and the human orthologue of the mouse ROSA26 locus. Additionally, the human orthologue of the mouse H11 locus may also be a suitable site for insertion using the composition and method of targeted integration disclosed herein. Further, collagen and HTRP gene loci may also be used as safe harbor for targeted integration. However, validation of each selected site has been shown to be necessary especially in stem cells for specific integration events, and optimization of insertion strategy including promoter election, exogenous gene sequence and arrangement, and construct design is often needed. [000209] For targeted in/dels, the editing site is often comprised in an endogenous gene whose expression and/or function is intended to be disrupted. In some embodiments, the endogenous gene comprising a targeted in/del is associated with immune response regulation and modulation. In some other embodiments, the endogenous gene comprising a targeted in/del is associated with targeting modality, receptors, signaling molecules, transcription factors, drug target candidates, immune response regulation and modulation, or proteins suppressing engraftment, trafficking, homing, viability, self-renewal, persistence, and/or survival of stem cells and/or progenitor cells, and the derived cells therefrom. [000210] As such, another aspect of the present invention provides a method of targeted integration in a selected locus including genome safe harbor or a preselected locus known or proven to be safe and well-regulated for continuous or temporal gene expression such as the B2M, TAP1, TAP2, tapasin, TRAC, or CD38 locus as provided herein; and the synthetic cells of the first and second populations of the composition of the invention may be produced using such method. In one embodiment, the genome safe harbor for the method of targeted integration comprises one or more desired integration site comprising AAVS1, CCR5, ROSA26, collagen, HTRP, H11, beta-2 microglobulin, CD38, GAPDH, TCR or RUNX1, or other loci meeting the criteria of a genome safe harbor. In some embodiments, the targeted integration is in one or more gene loci where the knock-down or knock-out of the gene as a result of the integration is desired, wherein such gene loci include, but are not limited to, B2M, TAP1, TAP2, tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR α or β constant region (TRAC or TRBC), NKG2A, NKG2D, CD25, CD38, CD44, CD54, CD56, CD58, CD69, CD71, OX40, 4-1BB, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, and TIGIT. [000211] In another embodiment, the method of targeted integration in a cell comprises introducing a construct comprising one or more exogenous polynucleotides to the cell, and introducing a ZFN expression cassette comprising a DNA-binding domain specific to a desired integration site to the cell to enable a ZFN-mediated insertion, wherein the desired integration site comprises AAVS1, CCR5, ROSA26, collagen, HTRP, H11, GAPDH, RUNX1, B2M, TAP1, TAP2, tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR α or β constant region, NKG2A, NKG2D, CD25, CD38, CD44, CD54, CD56, CD58, CD69, CD71, OX40, 4-1BB, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, or TIGIT. In yet another embodiment, the method of targeted integration in a cell comprises introducing a construct comprising one or more exogenous polynucleotides to the cell, and introducing a TALEN expression cassette comprising a DNA-binding domain specific to a desired integration site to the cell to enable a TALEN-mediated insertion, wherein the desired integration site comprises AAVS1, CCR5, ROSA26, collagen, HTRP, H11, GAPDH, RUNX1, B2M, TAP1, TAP2, tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR α or β constant region, NKG2A, NKG2D, CD25, CD38, CD44, CD54, CD56, CD58, CD69, CD71, OX40, 4-1BB, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, or TIGIT. In another embodiment, the method of targeted integration in a cell comprises introducing a construct comprising one or more exogenous polynucleotides to the cell, introducing a Cas9 expression cassette, and a gRNA comprising a guide sequence specific to a desired integration site to the cell to enable a Cas9-mediated insertion, wherein the desired integration site comprises AAVS1, CCR5, ROSA26, collagen, HTRP, H11, GAPDH, RUNX1, B2M, TAP1, TAP2, tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR α or β constant region, NKG2A, NKG2D, CD25, CD38, CD44, CD54, CD56, CD58, CD69, CD71, OX40, 4- 1BB, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, or TIGIT. In still another embodiment, the method of targeted integration in a cell comprises introducing a construct comprising one or more att sites of a pair of DICE recombinases to a desired integration site in the cell, introducing a construct comprising one or more exogenous polynucleotides to the cell, and introducing an expression cassette for DICE recombinases, to enable DICE-mediated targeted integration, wherein the desired integration site comprises AAVS1, CCR5, ROSA26, collagen, HTRP, H11, GAPDH, RUNX1, B2M, TAP1, TAP2, tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR α or β constant region, NKG2A, NKG2D, CD25, CD38, CD44, CD54, CD56, CD58, CD69, CD71, OX40, 4-1BB, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, or TIGIT. [000212] Further, as provided herein, the above method for targeted integration in a safe harbor is used to insert any polynucleotide of interest, for example, polynucleotides encoding safety switch proteins, targeting modality, receptors, signaling molecules, transcription factors, pharmaceutically active proteins and peptides, drug target candidates, and proteins promoting engraftment, trafficking, homing, viability, self-renewal, persistence, and/or survival of stem cells and/or progenitor cells. In some other embodiments, the construct comprising one or more exogenous polynucleotides further comprises one or more marker genes. In one embodiment, the exogenous polynucleotide in a construct of the invention is a suicide gene encoding safety switch protein. Suitable suicide gene systems for induced cell death include, but not limited to Caspase 9 (or caspase 3 or 7) and AP1903; thymidine kinase (TK) and ganciclovir (GCV); cytosine deaminase (CD) and 5-fluorocytosine (5-FC). Additionally, some suicide gene systems are cell type specific, for example, the genetic modification of T lymphocytes with the B-cell molecule CD20 allows their elimination upon administration of mAb Rituximab. Further, modified EGFR containing epitope recognized by cetuximab can be used to deplete genetically engineered cells when the cells are exposed to cetuximab. As such, one aspect of the invention provides a method of targeted integration of one or more suicide genes encoding safety switch proteins selected from caspase 9 (caspase 3 or 7), thymidine kinase, cytosine deaminase, modified EGFR, and B-cell CD20. [000213] In some embodiments, one or more exogenous polynucleotides integrated by the method described herein are driven by operatively-linked exogenous promoters comprised in the construct for targeted integration. The promoters may be inducible, or constructive, and may be temporal-, tissue- or cell type- specific. Suitable constructive promoters for methods of the invention include, but not limited to, cytomegalovirus (CMV), elongation factor 1α (EF1α), phosphoglycerate kinase (PGK), hybrid CMV enhancer/chicken β-actin (CAG) and ubiquitin C (UBC) promoters. In one embodiment, the exogenous promoter is CAG. [000214] The exogenous polynucleotides integrated by the method described herein may be driven by endogenous promoters in the host genome, at the integration site. In one embodiment, the method described herein is used for targeted integration of one or more exogenous polynucleotides at AAVS1 locus in the genome of a cell. In one embodiment, at least one integrated polynucleotide is driven by the endogenous AAVS1 promoter. In another embodiment, the method described herein is used for targeted integration at ROSA26 locus in the genome of a cell. In one embodiment, at least one integrated polynucleotide is driven by the endogenous ROSA26 promoter. In still another embodiment, the method of the invention is used for targeted integration at H11 locus in the genome of a cell. In one embodiment, at least one integrated polynucleotide is driven by the endogenous H11 promoter. In another embodiment, the method described herein is used for targeted integration at collagen locus in the genome of a cell. In one embodiment, at least one integrated polynucleotide is driven by the endogenous collagen promoter. In still another embodiment, the method of the invention is used for targeted integration at HTRP locus in the genome of a cell. In one embodiment, at least one integrated polynucleotide is driven by the endogenous HTRP promoter. Theoretically, only correct insertions at the desired location would enable gene expression of an exogenous gene driven by an endogenous promoter. [000215] In some embodiments, the one or more exogenous polynucleotides comprised in the construct for the methods of targeted integration are driven by one promoter. In some embodiments, the construct comprises one or more linker sequences between two adjacent polynucleotides driven by the same promoter to provide greater physical separation between the moieties and maximize the accessibility to enzymatic machinery. The linker peptide of the linker sequences may consist of amino acids selected to make the physical separation between the moieties (exogenous polynucleotides, and/or the protein or peptide encoded therefrom) more flexible or more rigid depending on the relevant function. The linker sequence may be cleavable by a protease or cleavable chemically to yield separate moieties. Examples of enzymatic cleavage sites in the linker include sites for cleavage by a proteolytic enzyme, such as enterokinase, Factor Xa, trypsin, collagenase, and thrombin. In some embodiments, the protease is one which is produced naturally by the host or it is exogenously introduced. Alternatively, the cleavage site in the linker may be a site capable of being cleaved upon exposure to a selected chemical, e.g., cyanogen bromide, hydroxylamine, or low pH. The optional linker sequence may serve a purpose other than the provision of a cleavage site. The linker sequence should allow effective positioning of the moiety with respect to another adjacent moiety for the moieties to function properly. The linker may also be a simple amino acid sequence of a sufficient length to prevent any steric hindrance between the moieties. In addition, the linker sequence may provide for post-translational modification including, but not limited to, e.g., phosphorylation sites, biotinylation sites, sulfation sites, γ-carboxylation sites, and the like. In some embodiments, the linker sequence is flexible so as not hold the biologically active peptide in a single undesired conformation. The linker may be predominantly comprised of amino acids with small side chains, such as glycine, alanine, and serine, to provide for flexibility. In some embodiments about 80 to 90 percent or greater of the linker sequence comprises glycine, alanine, or serine residues, particularly glycine and serine residues. In several embodiments, a G4S linker peptide separates the end-processing and endonuclease domains of the fusion protein. In other embodiments, a 2A linker sequence allows for two separate proteins to be produced from a single translation. Suitable linker sequences can be readily identified empirically. Additionally, suitable size and sequences of linker sequences also can be determined by conventional computer modeling techniques. In one embodiment, the linker sequence encodes a self-cleaving peptide. In one embodiment, the self-cleaving peptide is 2A. In some other embodiments, the linker sequence provides an Internal Ribosome Entry Sequence (IRES). In some embodiments, any two consecutive linker sequences are different. [000216] The method of introducing into cells a construct comprising exogenous polynucleotides for targeted integration can be achieved using a method of gene transfer to cells known per se. In one embodiment, the construct comprises backbones of viral vectors such as adenovirus vector, adeno-associated virus vector, retrovirus vector, lentivirus vector, Sendai virus vector. In some embodiments, the plasmid vectors are used for delivering and/or expressing the exogenous polynucleotides to target cells (e.g., pAl- 11, pXTl, pRc/CMV, pRc/RSV, pcDNAI/Neo) and the like. In some other embodiments, the episomal vector is used to deliver the exogenous polynucleotide to target cells. In some embodiments, recombinant adeno-associated viruses (rAAV) can be used for genetic engineering to introduce insertions, deletions or substitutions through homologous recombinations. Unlike lentiviruses, rAAVs do not integrate into the host genome. In addition, episomal rAAV vectors mediate homology- directed gene targeting at much higher rates compared to transfection of conventional targeting plasmids. In some embodiments, an AAV6 or AAV2 vector is used to introduce insertions, deletions or substitutions in a target site in the genome of iPSCs. In some embodiments, the genomically modified iPSCs and their derivative cells obtained using the methods and compositions described herein comprise at least one genotype listed in Table 1. III. Method of Obtaining and Maintaining Genome-engineered iPSCs [000217] In various embodiments, the present invention provides a method of obtaining and maintaining genome-engineered iPSCs comprising one or more targeted edits at one or more desired sites, wherein the one or more targeted edits remain intact and functional in expanded genome-engineered iPSCs or the iPSC-derived non-pluripotent cells at the respective selected editing site. The targeted editing introduces into the genome iPSC, and derivative cells therefrom, insertions, deletions, and/or substitutions (i.e., targeted integration and/or in/dels at selected sites). In comparison to direct engineering of patient-sourced, peripheral blood originated primary effector cells, the many benefits of obtaining genomically-engineered derivative cells through editing and differentiating iPSC as provided herein include, but are not limited to: unlimited source for engineered effector cells; no need for repeated manipulation of the effector cells, especially when multiple engineered modalities are involved; the obtained effector cells are rejuvenated for having elongated telomere and experiencing less exhaustion; the effector cell population is homogeneous in terms of editing site, copy number, and void of allelic variation, random mutations and expression variegation, largely due to the enabled clonal selection in engineered iPSCs as provided herein. [000218] In particular embodiments, the genome-engineered iPSCs comprising one or more targeted edits at one or more selected sites are maintained, passaged and expanded as single cells for an extended period in the cell culture medium shown in Table 2 as Fate Maintenance Medium (FMM), wherein the iPSCs retain the targeted editing and functional modification at the selected site(s). The components of the medium may be present in the medium in amounts within an optimal range shown in Table 2. The iPSCs cultured in FMM have been shown to continue to maintain their undifferentiated, and ground or naïve, profile; genomic stability without the need for culture cleaning or selection; and readily to give rise to all three somatic lineages, in vitro differentiation via embryoid bodies or monolayer (without formation of embryoid bodies); and in vivo differentiation by teratoma formation. See, for example, International Pub. No. WO2015/134652, the disclosure of which is incorporated herein by reference. Table 2: Exemplary media for iPSC reprogramming and maintenance feeder cells [000219] In some embodiments, the genome-engineered iPSCs comprising one or more targeted integration and/or in/dels are maintained, passaged and expanded in a medium comprising a MEK inhibitor, a GSK inhibitor, and a ROCK inhibitor, and free of, or essentially free of, TGFβ receptor/ALK5 inhibitors, wherein the iPSCs retain the intact and functional targeted edits at the selected sites. [000220] Another aspect of the invention provides a method of generating genome- engineered iPSCs through targeted editing of iPSCs; or through first generating genome- engineered non-pluripotent cells by targeted editing, and then reprogramming the selected/isolated genome-engineered non-pluripotent cells to obtain iPSCs comprising the same targeted editing as the non-pluripotent cells. A further aspect of the invention provides genome- engineering non-pluripotent cells which are concurrently undergoing reprogramming by introducing targeted integration and/or targeted in/dels to the cells, wherein the contacted non- pluripotent cells are under sufficient conditions for reprogramming, and wherein the conditions for reprogramming comprise contacting non-pluripotent cells with one or more reprogramming factors and small molecules. In various embodiments of the method for concurrent genome- engineering and reprogramming, the targeted integration and/or targeted in/dels may be introduced to the non-pluripotent cells prior to, or essentially concomitantly with, initiating reprogramming by contacting the non-pluripotent cells with one or more reprogramming factors and optionally one or more small molecules. [000221] In some embodiments, to concurrently genome-engineer and reprogram non- pluripotent cells, the targeted integration and/or in/dels may also be introduced to the non- pluripotent cells after the multi-day process of reprogramming is initiated by contacting the non- pluripotent cells with one or more reprogramming factors and small molecules, and wherein the vectors carrying the constructs are introduced before the reprogramming cells present stable expression of one or more endogenous pluripotent genes including, but not limited to, SSEA4, Tra181 and CD30. [000222] In some embodiments, the reprogramming is initiated by contacting the non- pluripotent cells with at least one reprogramming factor, and optionally a combination of a TGFβ receptor/ALK inhibitor, a MEK inhibitor, a GSK3 inhibitor and a ROCK inhibitor (FRM; Table 2). In some embodiments, the genome-engineered iPSCs produced through any methods above are further maintained and expanded using a mixture comprising a combination of a MEK inhibitor, a GSK3 inhibitor and a ROCK inhibitor (FMM; Table 2). [000223] In some embodiments of the method of generating genome-engineered iPSCs, the method comprises: genomically engineering an iPSC by introducing one or more targeted integrations and/or in/dels into iPSCs to obtain genome-engineered iPSCs having at least one genotype listed in Table 1. Alternatively, the method of generating genome-engineered iPSCs comprises: (a) introducing one or more targeted edits into non-pluripotent cells to obtain genome-engineered non-pluripotent cells comprising targeted integrations and/or in/dels at selected sites, and (b) contacting the genome-engineered non-pluripotent cells with one or more reprogramming factors, and optionally a small molecule composition comprising a TGFβ receptor/ALK inhibitor, a MEK inhibitor, a GSK3 inhibitor and/or a ROCK inhibitor, to obtain genome-engineered iPSCs comprising targeted integrations and/or in/dels at selected sites. Alternatively, the method of generating genome-engineered iPSCs comprises: (a) contacting non-pluripotent cells with one or more reprogramming factors, and optionally a small molecule composition comprising a TGFβ receptor/ALK inhibitor, a MEK inhibitor, a GSK3 inhibitor and/or a ROCK inhibitor to initiate the reprogramming of the non-pluripotent cells; (b) introducing one or more targeted integrations and/or in/dels into the reprogramming non- pluripotent cells for genome-engineering; and (c) obtaining genome-engineered iPSCs comprising targeted integrations and/or in/dels at selected sites. Any of the above methods may further comprise single cell sorting of the genome-engineered iPSCs to obtain a clonal iPSC. Through clonal expansion of the genome-engineered iPSCs, a master cell bank is generated to comprise single cell sorted and expanded clonal engineered iPSCs having at least one phenotype as provided herein. The master cell bank is subsequently cryopreserved, providing a platform for additional iPSC engineering and a renewable source for manufacturing off-the-shelf, engineered, homogeneous cell therapy products, which are well-defined and uniform in composition, and can be mass produced at significant scale in a cost-effective manner. [000224] The reprogramming factors are selected from the group consisting of OCT4, SOX2, NANOG, KLF4, LIN28, C-MYC, ECAT1, UTF1, ESRRB, SV40LT, HESRG, CDH1, TDGF1, DPPA4, DNMT3B, ZIC3, L1TD1, and any combinations thereof, as disclosed in International Pub. Nos. WO2015/134652 and WO2017/066634, the disclosures of which are incorporated herein by reference. The one or more reprogramming factors may be in the form of a polypeptide. The reprogramming factors may also be in the form of polynucleotides encoding the reprogramming factors, and thus may be introduced to the non-pluripotent cells by vectors such as, a retrovirus, a Sendai virus, an adenovirus, an episome, a plasmid, and a mini-circle. In particular embodiments, the one or more polynucleotides encoding at least one reprogramming factor are introduced by a lentiviral vector. In some embodiments, the one or more polynucleotides introduced by an episomal vector. In various other embodiments, the one or more polynucleotides are introduced by a Sendai viral vector. In some embodiments, the one or more polynucleotides introduced by a combination of plasmids. See, for example, International Pub. No. WO2019/075057A1, the disclosure of which is incorporated herein by reference. [000225] In some embodiments, the non-pluripotent cells are transfected with multiple constructs comprising different exogenous polynucleotides and/or different promoters by multiple vectors for targeted integration at the same or different selected sites. These exogenous polynucleotides may comprise a suicide gene, or a gene encoding targeting modality, receptors, signaling molecules, transcription factors, pharmaceutically active proteins and peptides, drug target candidates, or a gene encoding a protein promoting engraftment, trafficking, homing, viability, self-renewal, persistence, and/or survival of the iPSCs or derivative cells therefrom. In some embodiments, the exogenous polynucleotides encode RNA, including but not limited to siRNA, shRNA, miRNA and antisense nucleic acids. These exogenous polynucleotides may be driven by one or more promoters selected form the group consisting of constitutive promoters, inducible promoters, temporal-specific promoters, and tissue or cell type specific promoters. Accordingly, the polynucleotides are expressible when under conditions that activate the promoter, for example, in the presence of an inducing agent or in a particular differentiated cell type. In some embodiments, the polynucleotides are expressed in iPSCs and/or in cells differentiated from the iPSCs. In one embodiment, one or more suicide genes are driven by a constitutive promoter, for example Capase-9 driven by CAG. These constructs comprising different exogenous polynucleotides and/or different promoters can be transfected to non- pluripotent cells either simultaneously or consecutively. The non-pluripotent cells subjected to targeted integration of multiple constructs can simultaneously contact the one or more reprogramming factors to initiate the reprogramming concurrently with the genomic engineering, thereby obtaining genome-engineered iPSCs comprising multiple targeted integrations in the same pool of cells. As such, this robust method enables a concurrent reprogramming and engineering strategy to derive a clonal genomically-engineered iPSC with multiple modalities integrated to one or more selected target sites. In some embodiments, the genomically modified iPSCs and their derivative cells obtained using the methods and composition provided herein comprise at least one genotype listed in Table 1. IV. A method of Obtaining Synthetic Effector Cells by Differentiating Genome- engineered iPSC [000226] A further aspect of the present invention provides a method of in vivo differentiation of genome-engineered iPSCs by teratoma formation, wherein the differentiated cells derived in vivo from the genome-engineered iPSCs retain the intact and functional targeted edits including targeted integration(s) and/or in/dels at the desired site(s). In some embodiments, the differentiated cells derived in vivo from the genome-engineered iPSCs via teratoma formation comprise one or more inducible suicide genes integrated at one or more desired sites comprising AAVS1, CCR5, ROSA26, collagen, HTRP H11, beta-2 microglobulin, CD38, GAPDH, TCR or RUNX1, or other loci meeting the criteria of a genome safe harbor. In some other embodiments, the differentiated cells derived in vivo from the genome-engineered iPSCs via teratoma formation comprise polynucleotides encoding targeting modalities, or encoding proteins promoting trafficking, homing, viability, self-renewal, persistence, and/or survival of stem cells and/or progenitor cells. In some embodiments, the differentiated cells derived in vivo from the genome-engineered iPSCs via teratoma formation comprising one or more inducible suicide genes further comprise one or more in/dels in endogenous genes associated with immune response regulation and mediation. In some embodiments, the in/del is comprised in one or more endogenous checkpoint genes. In some embodiments, the in/del is comprised in one or more endogenous T cell receptor genes. In some embodiments, the in/del is comprised in one or more endogenous MHC class I suppressor genes. In some embodiments, the in/del is comprised in one or more endogenous genes associated with the major histocompatibility complex. In some embodiments, the in/del is comprised in one or more endogenous genes including, but not limited to, AAVS1, CCR5, ROSA26, collagen, HTRP, H11, GAPDH, RUNX1, B2M, TAP1, TAP2, tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR α or β constant region, NKG2A, NKG2D, CD25, CD38, CD44, CD54, CD56, CD58, CD69, CD71, OX40, 4-1BB, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, and TIGIT. In one embodiment, the genome- engineered iPSCs comprising one or more exogenous polynucleotides at selected site(s) further comprise a targeted edit in a B2M (beta-2-microglobulin) encoding gene. [000227] In particular embodiments, the genome-engineered iPSCs comprising one or more genetic modifications as provided herein are used to derive hematopoietic cell lineages or any other specific cell types in vitro, wherein the derived non-pluripotent cells retain the functional genetic modifications including targeted editing at the selected site(s). In some embodiments, the genome-engineered iPSCs used to derive hematopoietic cell lineages or any other specific cell types in vitro are master cell bank cells that are cryopreserved and thawed right before their usage. In one embodiment, the genome-engineered iPSC-derived cells include, but are not limited to, mesodermal cells with definitive hemogenic endothelium (HE) potential, definitive HE, CD34 hematopoietic cells, hematopoietic stem and progenitor cells, hematopoietic multipotent progenitors (MPP), T cell progenitors, NK cell progenitors, myeloid cells, neutrophil progenitors, T cells, NKT cells, NK cells, B cells, neutrophils, dendritic cells, and macrophages, wherein the cells derived from the genome-engineered iPSCs retain the functional genetic modifications including targeted editing at the desired site(s). [000228] Applicable differentiation methods and compositions for obtaining iPSC-derived hematopoietic cell lineages include those depicted in, for example, International Pub. No. WO2017/078807, the disclosure of which is incorporated herein by reference. As provided, the methods and compositions for generating hematopoietic cell lineages are through definitive hemogenic endothelium (HE) derived from pluripotent stem cells, including iPSCs under serum- free, feeder-free, and/or stromal-free conditions and in a scalable and monolayer culturing platform without the need of EB formation. Cells that may be differentiated according to the provided methods range from pluripotent stem cells, to progenitor cells that are committed to particular terminally differentiated cells and transdifferentiated cells, and to cells of various lineages directly transitioned to hematopoietic fate without going through a pluripotent intermediate. Similarly, the cells that are produced by differentiating stem cells range from multipotent stem or progenitor cells, to terminally differentiated cells, and to all intervening hematopoietic cell lineages. [000229] The methods for differentiating and expanding cells of the hematopoietic lineage from pluripotent stem cells in monolayer culturing comprise contacting the pluripotent stem cells with a BMP pathway activator, and optionally, bFGF. As provided, the pluripotent stem cell-derived mesodermal cells are obtained and expanded without forming embryoid bodies from pluripotent stem cells. The mesodermal cells are then subjected to contact with a BMP pathway activator, bFGF, and a WNT pathway activator to obtain expanded mesodermal cells having definitive hemogenic endothelium (HE) potential without forming embryoid bodies from the pluripotent stem cells. By subsequent contact with bFGF, and optionally, a ROCK inhibitor, and/or a WNT pathway activator, the mesodermal cells having definitive HE potential are differentiated to definitive HE cells, which are also expanded during differentiation. [000230] The methods provided herein for obtaining cells of the hematopoietic lineage are superior to EB-mediated pluripotent stem cell differentiation, because EB formation leads to modest to minimal cell expansion, does not allow monolayer culturing which is important for many applications requiring homogeneous expansion and homogeneous differentiation of the cells in a population, and is laborious and of low efficiency. [000231] The provided monolayer differentiation platform facilitates differentiation towards definitive hemogenic endothelium resulting in the derivation of hematopoietic stem cells and differentiated progeny such as T, B, NKT and NK cells. The monolayer differentiation strategy combines enhanced differentiation efficiency with large-scale expansion, and enables the delivery of a therapeutically relevant number of pluripotent stem cell-derived hematopoietic cells for various therapeutic applications. Further, monolayer culturing using the methods provided herein leads to functional hematopoietic lineage cells that enable a full range of in vitro differentiation, ex vivo modulation, and in vivo long term hematopoietic self-renewal, reconstitution and engraftment. As provided, the iPSC-derived hematopoietic lineage cells include, but are not limited to, definitive hemogenic endothelium, hematopoietic multipotent progenitor cells, hematopoietic stem and progenitor cells, T cell progenitors, NK cell progenitors, T cells, NK cells, NKT cells, B cells, macrophages, and neutrophils. [000232] Thus, in various embodiments, the method for directing differentiation of pluripotent stem cells into cells of a definitive hematopoietic lineage, comprises: (i) contacting pluripotent stem cells with a composition comprising a BMP activator, and optionally bFGF, to initiate differentiation and expansion of mesodermal cells from the pluripotent stem cells; (ii) contacting the mesodermal cells with a composition comprising a BMP activator, bFGF, and a GSK3 inhibitor, wherein the composition is optionally free of TGFβ receptor/ALK inhibitor, to initiate differentiation and expansion of mesodermal cells having definitive HE potential from the mesodermal cells; (iii) contacting the mesodermal cells having definitive HE potential with a composition comprising a ROCK inhibitor; one or more growth factors and cytokines selected from the group consisting of bFGF, VEGF, SCF, IGF, EPO, IL6, and IL11; and optionally, a Wnt pathway activator, wherein the composition is optionally free of TGFβ receptor/ALK inhibitor, to initiate differentiation and expansion of definitive hemogenic endothelium from pluripotent stem cell-derived mesodermal cells having definitive hemogenic endothelium potential. [000233] In some embodiments, the method further comprises contacting pluripotent stem cells with a composition comprising a MEK inhibitor, a GSK3 inhibitor, and a ROCK inhibitor, wherein the composition is free of TGFβ receptor/ALK inhibitors, to seed and expand the pluripotent stem cells. In some embodiments, the pluripotent stem cells are iPSCs, or naïve iPSCs, or iPSCs comprising one or more genetic imprints; and the one or more genetic imprints comprised in the iPSCs are retained in the hematopoietic cells differentiated therefrom. In some embodiments of the method for directing differentiation of pluripotent stem cells into cells of a hematopoietic lineage, the differentiation of the pluripotent stem cells into cells of hematopoietic lineage is void of generation of embryoid bodies, and is in a monolayer culturing form. [000234] In some embodiments of the above method, the obtained pluripotent stem cell- derived definitive hemogenic endothelium cells are CD34 + . In some embodiments, the obtained definitive hemogenic endothelium cells are CD34 + CD43-. In some embodiments, the definitive hemogenic endothelium cells are CD34 + CD43-CXCR4-CD73-. In some embodiments, the definitive hemogenic endothelium cells are CD34 + CXCR4-CD73-. In some embodiments, the definitive hemogenic endothelium cells are CD34 + CD43-CD93-. In some embodiments, the definitive hemogenic endothelium cells are CD34 + CD93-. [000235] In some embodiments of the above method, the method further comprises (i) contacting pluripotent stem cell-derived definitive hemogenic endothelium with a composition comprising a ROCK inhibitor; one or more growth factors and cytokines selected from the group consisting of VEGF, bFGF, SCF, Flt3L, TPO, and IL7; and optionally a BMP activator; to initiate the differentiation of the definitive hemogenic endothelium to pre-T cell progenitors; and optionally, (ii) contacting the pre-T cell progenitors with a composition comprising one or more growth factors and cytokines selected from the group consisting of SCF, Flt3L, and IL7, but free of one or more of VEGF, bFGF, TPO, BMP activators and ROCK inhibitors, to initiate the differentiation of the pre-T cell progenitors to T cell progenitors or T cells. In some embodiments of the method, the pluripotent stem cell-derived T cell progenitors are CD34 + CD45 + CD7 + . In some embodiments of the method, the pluripotent stem cell-derived T cell progenitors are CD45 + CD7 + . [000236] In yet some embodiments of the above method for directing differentiation of pluripotent stem cells into cells of a hematopoietic lineage, the method further comprises: (i) contacting pluripotent stem cell-derived definitive hemogenic endothelium with a composition comprising a ROCK inhibitor; one or more growth factors and cytokines selected from the group consisting of VEGF, bFGF, SCF, Flt3L, TPO, IL3, IL7, and IL15; and optionally, a BMP activator, to initiate differentiation of the definitive hemogenic endothelium to pre-NK cell progenitor; and optionally, (ii) contacting pluripotent stem cells-derived pre-NK cell progenitors with a composition comprising one or more growth factors and cytokines selected from the group consisting of SCF, Flt3L, IL3, IL7, and IL15, wherein the medium is free of one or more of VEGF, bFGF, TPO, BMP activators and ROCK inhibitors, to initiate differentiation of the pre-NK cell progenitors to NK cell progenitors or NK cells. In some embodiments, the pluripotent stem cell-derived NK progenitors are CD3-CD45 + CD56 + CD7 + . In some embodiments, the pluripotent stem cell-derived NK cells are CD3-CD45 + CD56 + , and optionally further defined by being NKp46 + , CD57 + and CD16 + . [000237] Therefore, using the above differentiation methods, one may obtain one or more populations of iPSC-derived hematopoietic cells: (i) CD34 + HE cells (iCD34), using one or more culture medium selected from iMPP-A, iTC-A2, iTC-B2, iNK-A2, and iNK-B2; (ii) definitive hemogenic endothelium (iHE), using one or more culture medium selected from iMPP-A, iTC-A2, iTC-B2, iNK-A2, and iNK-B2; (iii) definitive HSCs, using one or more culture medium selected from iMPP-A, iTC-A2, iTC-B2, iNK-A2, and iNK-B2; (iv) multipotent progenitor cells (iMPP), using iMPP-A; (v) T cell progenitors (ipro-T), using one or more culture medium selected from iTC-A2, and iTC-B2; (vi) T cells (iTC), using iTC-B2; (vii) NK cell progenitors (ipro-NK), using one or more culture medium selected from iNK-A2, and iNK- B2; and/or (viii) NK cells (iNK), and iNK-B2. In some embodiments, the medium: a. iCD34-C comprises a ROCK inhibitor, one or more growth factors and cytokines selected from the group consisting of bFGF, VEGF, SCF, IL6, IL11, IGF, and EPO, and optionally, a Wnt pathway activator; and is free of TGFβ receptor/ALK inhibitor; b. iMPP-A comprises a BMP activator, a ROCK inhibitor, and one or more growth factors and cytokines selected from the group consisting of TPO, IL3, GMCSF, EPO, bFGF, VEGF, SCF, IL6, Flt3L and IL11; c. iTC-A2 comprises a ROCK inhibitor; one or more growth factors and cytokines selected from the group consisting of SCF, Flt3L, TPO, and IL7; and optionally, a BMP activator; d. iTC-B2 comprises one or more growth factors and cytokines selected from the group consisting of SCF, Flt3L, and IL7; e. iNK-A2 comprises a ROCK inhibitor, and one or more growth factors and cytokines selected from the group consisting of SCF, Flt3L, TPO, IL3, IL7, and IL15; and optionally, a BMP activator, and f. iNK-B2 comprises one or more growth factors and cytokines selected from the group consisting of SCF, Flt3L, IL7 and IL15. [000238] In some embodiments, the genome-engineered iPSC-derived cells obtained from the above methods comprise one or more inducible suicide gene integrated at one or more desired integration sites comprising AAVS1, CCR5, ROSA26, collagen, HTRP, H11, GAPDH, RUNX1, B2M, TAP1, TAP2, tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR α or β constant region, NKG2A, NKG2D, CD25, CD38, CD44, CD54, CD56, CD58, CD69, CD71, OX40, 4-1BB, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, and TIGIT, or other loci meeting the criteria of a genome safe harbor. In some other embodiments, the genome- engineered iPSC-derived cells comprise polynucleotides encoding safety switch proteins, targeting modality, receptors, signaling molecules, transcription factors, pharmaceutically active proteins and peptides, drug target candidates, or proteins promoting trafficking, homing, viability, self-renewal, persistence, and/or survival of stem cells and/or progenitor cells. In some embodiments, the genome-engineered iPSC-derived cells comprising one or more suicide genes further comprise one or more in/dels comprised in one or more endogenous genes associated with immune response regulation and mediation, including, but not limited to, checkpoint genes, endogenous T cell receptor genes, and MHC class I suppressor genes. In one embodiment, the genome-engineered iPSC-derived cells comprising one or more suicide genes further comprise an in/del in B2M gene, wherein the B2M is knocked-out. [000239] Additionally, applicable dedifferentiation methods and compositions for obtaining genomic-engineered hematopoietic cells of a first fate to genomic-engineered hematopoietic cells of a second fate include those depicted in, for example, International Pub. No. WO2011/159726, the disclosure of which is incorporated herein by reference. The method and composition provided therein allows partially reprogramming a starting non-pluripotent cell to a non-pluripotent intermediate cell by limiting the expression of endogenous Nanog gene during reprogramming; and subjecting the non-pluripotent intermediate cell to conditions for differentiating the intermediate cell into a desired cell type. In some embodiments, the genomically modified iPSCs and their derivative cells obtained using the methods and composition herein comprise at least one genotype listed in Table 1. V. Therapeutic Use of Combined Synthetic Effector Cell Types Differentiated from Genetically Engineered iPSCs [000240] The present invention provides, in some embodiments, a composition comprising two or more synthetic effector cell types or two or more populations of different synthetic effector cell types, where each of the synthetic effector cells have been differentiated from genomically engineered iPSCs using the methods and compositions as disclosed. In some embodiments, the engineered iPSCs comprise one or more targeted genetic edits which are retainable in the iPSC-derived effector cells, resulting in synthetic effector cells having enhanced functional modalities, wherein the genetically engineered iPSCs and derivative synthetic effector cells are suitable for cell-based adoptive therapies. In one embodiment, the enhanced synthetic effector cells comprise iPSC-derived CD34 cells. In one embodiment, the enhanced synthetic effector cells comprise iPSC-derived HSC cells. In one embodiment, the enhanced synthetic effector cells comprise iPSC-derived proT or T cells. In one embodiment, the enhanced synthetic effector cells comprise iPSC-derived proNK or NK cells. In one embodiment, the enhanced synthetic effector cells comprise iPSC-derived immune regulatory cells or myeloid derived suppressor cells (MDSCs). [000241] In some embodiments, the iPSC-derived enhanced synthetic effector cells are further modulated ex vivo for improved therapeutic potential. In one embodiment, at least one of the isolated populations or subpopulations of enhanced synthetic effector cells that have been derived from iPSCs comprises an increased number or ratio of naïve T cells, stem cell memory T cells, and/or central memory T cells. In one embodiment, at least one of the isolated populations or subpopulations of enhanced synthetic effector cells that have been derived from iPSCs comprises an increased number or ratio of type I NKT cells. In another embodiment, at least one of the isolated populations or subpopulations of enhanced synthetic effector cells that have been derived from iPSCs comprises an increased number or ratio of adaptive NK cells. In some embodiments, at least one of the isolated populations or subpopulations of enhanced synthetic CD34 cells, HSC cells, T cells, NK cells, or myeloid derived suppressor cells derived from iPSCs is allogeneic. In some other embodiments, at least one of the isolated populations or subpopulations of enhanced synthetic CD34 cells, HSC cells, T cells, NK cells, or MDSCs derived from iPSCs is autologous. [000242] In some embodiments of the composition comprising two or more synthetic effector cell types or two or more populations of different synthetic effector cell types, where each of the synthetic effector cells have been differentiated from genomically engineered iPSCs, the first type of synthetic effector cell is a functionally enhanced iPSC-derived T cell, and the second type of synthetic effector cell is a functionally enhanced iPSC-derived NK cell. In some embodiments, the functionally enhanced iPSC-derived T cells comprise at least a first CAR. In some embodiments, the functionally enhanced iPSC-derived NK cell comprises at least a second CAR, and one or both of a CD16 variant and a partial or full length of an exogenous cell surface expressed cytokine and/or a receptor thereof. In some embodiments, the two different types of synthetic effector cells are in two separate populations. In some embodiments, the two separate populations of synthetic effector cells are combined into a mixed population (i.e., the two populations are mixed). [000243] In some embodiments, the iPSCs for differentiation comprise additional genetic imprints selected to convey desirable therapeutic attributes in derived effector cells, provided that cell development biology during differentiation is not disrupted, and provided that the genetic imprints are retained and functional in the differentiated hematopoietic cells derived from said iPSC. [000244] In some embodiments, the genetic imprints of the pluripotent stem cells comprise (i) one or more genetically modified modalities obtained through genomic insertion, deletion or substitution in the genome of the pluripotent cells during or after reprogramming a non- pluripotent cell to iPSC; or (ii) one or more retainable therapeutic attributes of a source specific immune cell that is donor-, disease-, or treatment response- specific, and wherein the pluripotent cells are reprogrammed from the source specific immune cell, wherein the iPSC retain the source therapeutic attributes, which are also comprised in the iPSC-derived hematopoietic lineage cells. [000245] In some embodiments, the genetically modified modalities comprise one or more of: safety switch proteins, targeting modalities, receptors, signaling molecules, transcription factors, pharmaceutically active proteins and peptides, drug target candidates; or proteins promoting engraftment, trafficking, homing, viability, self-renewal, persistence, immune response regulation and modulation, and/or survival of the iPSCs or derivative cells therefrom. [000246] In still some other embodiments, the iPSC-derived hematopoietic lineage cells comprise the therapeutic attributes of the source specific immune cell relating to a combination of at least two of the following: (i) expression of one or more antigen targeting receptors; (ii) modified HLA; (iii) resistance to tumor microenvironment; (iv) recruitment of bystander immune cells and immune modulations; (iv) improved on-target specificity with reduced off- tumor effect; and (v) improved homing, persistence, cytotoxicity, or antigen escape rescue. [000247] In some embodiments, the synthetic effector cells described herein and/or compositions comprising first and second populations of synthetic effector cells are useful in treating and/or ameliorating various diseases. In one embodiment of the method of treating a subject using the composition as provided herein, the method comprises administering a first synthetic cell population that comprises iPSC-derived NK cells, wherein the iPSC-derived NK cells comprise: (a) a high affinity non-cleavable CD16 (hnCD16) or a variant thereof; and (b) one or both of a first chimeric antigen receptor (CAR), and a partial or full length peptide of an exogenous cell surface expressed cytokine or a receptor thereof; and administering a second synthetic cell population that comprises iPSC-derived T cells, wherein the iPSC-derived T cells comprise: at least a second chimeric antigen receptor (CAR), wherein the second CAR is expressed under the control of an endogenous promoter of said TCR locus, and wherein the first CAR and the second CAR have the same or different targeting specificity. This method, as disclosed, provides, among many other advantages, durable responses in cytotoxicity, multi- antigen targeting, and is effective to overcome tumor antigen escape, and has diverse applications in multiple lines of indication. [000248] In some embodiments, the iPSC-derived hematopoietic cells comprise a genotype listed in Table 1, and said cells express at least one cytokine and/or its receptor comprising IL2, IL4, IL6, IL7, IL9, IL10, IL11, IL12, IL15, IL18, or IL21, or any modified protein thereof, and express at least a CAR. In some embodiments, the engineered expression of the cytokine(s) and the CAR(s) is NK cell specific. In some other embodiments, the engineered expression of the cytokine(s) and the CAR(s) is T cell specific. In one embodiment, the CAR of the derivative hematopoietic cell comprises a binding domain recognizing any one of CD19, BCMA, CD20, CD22, CD38, CD123, HER2, CD52, EGFR, GD2, and PDL1 antigen. In some embodiments, the antigen specific iPSC-derived effector cells target a liquid tumor. In some embodiments, the antigen specific iPSC-derived effector cells target a solid tumor/cancer. In some embodiments, the antigen specific iPSC-derived effector cells are capable of rescuing tumor antigen escape. [000249] A variety of diseases may be treated and/or ameliorated by introducing two or more types of the synthetic effector cells of the invention to a subject suitable for adoptive cell therapy. In some embodiments, the two or more types of iPSC-derived hematopoietic cells are provided for allogeneic adoptive cell therapies. Additionally, the present invention provides, in some embodiments, therapeutic use of the above therapeutic compositions by introducing the composition comprising two or more types of iPSC-derived effector cells to a subject suitable for adoptive cell therapy, wherein the subject has an autoimmune disorder; a hematological malignancy; a solid tumor; or an infection associated with HIV, RSV, EBV, CMV, adenovirus, or BK polyomavirus. [000250] Examples of hematological malignancies include, but are not limited to, acute and chronic leukemias (acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), lymphomas, non-Hodgkin lymphoma (NHL), Hodgkin’s disease, multiple myeloma, and myelodysplastic syndromes. Examples of solid cancers include, but are not limited to, cancer of the brain, prostate, breast, lung, colon, uterus, skin, liver, bone, pancreas, ovary, testes, bladder, kidney, head, neck, stomach, cervix, rectum, larynx, and esophagus. Examples of various autoimmune disorders include, but are not limited to, alopecia areata, autoimmune hemolytic anemia, autoimmune hepatitis, dermatomyositis, diabetes (type 1), some forms of juvenile idiopathic arthritis, glomerulonephritis, Graves’ disease, Guillain-Barré syndrome, idiopathic thrombocytopenic purpura, myasthenia gravis, some forms of myocarditis, multiple sclerosis, pemphigus/pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma/systemic sclerosis, Sjögren’s syndrome, systemic lupus, erythematosus, some forms of thyroiditis, some forms of uveitis, vitiligo, granulomatosis with polyangiitis (Wegener’s). Examples of viral infections include, but are not limited to, HIV- (human immunodeficiency virus), HSV- (herpes simplex virus), KSHV- (Kaposi’s sarcoma-associated herpesvirus), RSV- (Respiratory Syncytial Virus), EBV- (Epstein-Barr virus), CMV- (cytomegalovirus), VZV (Varicella zoster virus), adenovirus-, a lentivirus-, a BK polyomavirus- associated disorders. [000251] The treatment using a composition comprising two or more types of iPSC- derived hematopoietic lineage cells as disclosed herein could be carried out upon symptom presentation, or for relapse prevention or treatment. The terms “treating,” “treatment,” and the like are used herein to generally mean obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease. “Treatment” as used herein covers any intervention of a disease in a subject and includes: preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; and inhibiting the disease, i.e., arresting its development; or relieving the disease, i.e., causing regression of the disease. The composition comprising two or more types of iPSC-derived hematopoietic lineage cells may be administered before, during or after the onset of a disease or an injury. Treatment of ongoing disease, where the treatment stabilizes or reduces the undesirable clinical symptoms of the patient, is also of particular interest. In particular embodiments, the subject in need of a treatment has a disease, a condition, and/or an injury that can be contained, ameliorated, and/or improved in at least one associated symptom by a cell therapy. Certain embodiments contemplate that a subject in need of cell therapy, includes, but is not limited to, a candidate for bone marrow or stem cell transplantation, a subject who has received chemotherapy or irradiation therapy, a subject who has or is at risk of having a hyperproliferative disorder or a cancer, e.g., a hyperproliferative disorder or a cancer of hematopoietic system, a subject having or at risk of developing a tumor, e.g., a solid tumor, a subject who has or is at risk of having a viral infection or a disease associated with a viral infection. [000252] When evaluating responsiveness to the treatment with a composition comprising two or more types of iPSC-derived hematopoietic lineage cells as disclosed herein, the response can be measured by criteria comprising at least one of: clinical benefit rate, survival until mortality, pathological complete response, semi-quantitative measures of pathologic response, clinical complete remission, clinical partial remission, clinical stable disease, recurrence-free survival, metastasis free survival, disease free survival, circulating tumor cell decrease, circulating marker response, and RECIST (Response Evaluation Criteria In Solid Tumors) criteria. [000253] The therapeutic composition comprising two or more types of iPSC-derived hematopoietic lineage cells as disclosed herein can be administered to a subject before, during, and/or after other treatments. As such, a method of combinational therapy is provided, which can involve the administration or preparation of the two or more iPSC-derived effector cell types before, during, and/or after the use of an additional therapeutic agent. In one embodiment, the composition comprises two or more synthetic effector cell types derived from genomically engineered iPSCs, wherein the composition comprises at least one or two or more of: iPSC- derived NK cells, iPSC-derived T cells, iPSC-derived CD34 + HE cells, iPSC-derived HSCs, iPSC-derived NKT cells, iPSC-derived B cells, iPSC-derived T progenitors, iPSC-derived NK progenitors, and iPSC-derived MDSCs, which cells are made by the methods and compositions disclosed herein. A composition comprising two or more types of iPSC-derived hematopoietic lineage cells as disclosed herein can be administered concurrently or consecutively by intravenous, intraperitoneal, enteral, or tracheal administration methods. In some embodiments, when the two types of derivative effector cells are administered concurrently, each type of cell is in its respective separate population, or the two types of derivative effector cells are administered in one mixed population. In some embodiments, each population of the composition is administered concurrently or consequently with one or more suitable therapeutic agents to effect the desired treatment goals. [000254] As provided above, the one or more additional therapeutic agents comprise a peptide, a cytokine, a checkpoint inhibitor, a mitogen, a growth factor, a small RNA, a dsRNA (double stranded RNA), mononuclear blood cells, feeder cells, feeder cell components or replacement factors thereof, a vector comprising one or more polynucleic acids of interest, an antibody, a chemotherapeutic agent or a radioactive moiety, or an immunomodulatory drug (IMiD). Immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide stimulate both NK cells and T cells. As provided herein, IMiDs may be used with the iPSC-derived therapeutic effector cells for cancer treatments. [000255] The administration of the two or more types of iPSC-derived effector cells can be separated in time from the administration of an additional therapeutic agent by hours, days, or even weeks. Additionally, or alternatively, the administration can be combined with other biologically active agents or modalities such as, but not limited to, an antineoplastic agent, or a non-drug therapy, such as, surgery. [000256] In some embodiments of a combinational cell therapy, the therapeutic composition comprising the two or more types of iPSC-derived hematopoietic lineage cells provided herein comprises an additional therapeutic agent that is an antibody, or an antibody fragment. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody may be a humanized antibody, a humanized monoclonal antibody, or a chimeric antibody. In some embodiments, the antibody, or antibody fragment, specifically binds to a viral antigen. In other embodiments, the antibody, or antibody fragment, specifically binds to a tumor antigen. In some embodiments, the tumor or viral specific antigen activates the administered iPSC-derived hematopoietic lineage cells to enhance their killing ability. In some embodiments, the antibodies suitable for combinational treatment as an additional therapeutic agent to the administered iPSC-derived hematopoietic lineage cells include, but are not limited to, anti-CD20 (e.g., rituximab, veltuzumab, ofatumumab, ublituximab, ocaratuzumab, obinutuzumab, ibritumomab, ocrelizumab), anti-CD22 (inotuzumab, moxetumomab, epratuzumab), anti-HER2 (e.g., trastuzumab, pertuzumab), anti-CD52 (e.g., alemtuzumab), anti-EGFR (e.g., certuximab), anti-GD2 (e.g., dinutuximab), anti-PDL1 (e.g., avelumab), anti-CD38 (e.g., daratumumab, isatuximab, MOR202), anti-CD123 (e.g., 7G3, CSL362), anti-SLAMF7 (elotuzumab), and their humanized or Fc modified variants or fragments or their functional equivalents or biosimilars. [000257] In some embodiments, the additional therapeutic agent comprises one or more checkpoint inhibitors. Checkpoints are cell molecules, often cell surface molecules, capable of suppressing or downregulating immune responses when not inhibited. Checkpoint inhibitors are antagonists capable of reducing checkpoint gene expression or gene products, or deceasing activity of checkpoint molecules. Suitable checkpoint inhibitors for combination therapy with the derivative effector cells provided herein include, but are not limited to, antagonists of PD-1 (Pdcdl, CD279), PDL-1 (CD274), TIM-3 (Havcr2), TIGIT (WUCAM and Vstm3), LAG-3 (Lag3, CD223), CTLA-4 (Ctla4, CD152), 2B4 (CD244), 4-1BB (CD137), 4-1BBL (CD137L), A 2A R, BATE, BTLA, CD39 (Entpdl), CD47, CD73 (NT5E), CD94, CD96, CD160, CD200, CD200R, CD274, CEACAM1, CSF-1R, Foxpl, GARP, HVEM, IDO, EDO, TDO, LAIR-1, MICA/B, NR4A2, MAFB, OCT-2 (Pou2f2), retinoic acid receptor alpha (Rara), TLR3, VISTA, NKG2A/HLA-E, and inhibitory KIR (for example, 2DL1, 2DL2, 2DL3, 3DL1, and 3DL2). [000258] Some embodiments of the combination therapy comprising the provided two or more types of derivative effector cells further comprise at least one inhibitor targeting a checkpoint molecule. Some other embodiments of the combination therapy with the provided two or more types of derivative effector cells comprise two, three or more inhibitors such that two, three, or more checkpoint molecules are targeted. In some embodiments, the two types of effector cells for combination therapy as described herein include a population of derivative T cells and a population of derivative NK cells as provided. In some embodiments, the derivative T or NK cells are functionally enhanced as provided herein. In some embodiments, the two, three or more checkpoint inhibitors may be administered in a combination therapy with, before, or after the administering of the two types of derivative effector cells. In some embodiments, the two or more checkpoint inhibitors are administered at the same time, or one at a time (sequential). [000259] In some embodiments, the antagonist inhibiting any of the above checkpoint molecules is an antibody. In some embodiments, the checkpoint inhibitory antibodies may be murine antibodies, human antibodies, humanized antibodies, a camel Ig, a shark heavy-chain- only antibody (VNAR), Ig NAR, chimeric antibodies, recombinant antibodies, or antibody fragments thereof. Non-limiting examples of antibody fragments include Fab, Fab′, F(ab′)2, F(ab′)3, Fv, single chain antigen binding fragments (scFv), (scFv)2, disulfide stabilized Fv (dsFv), minibody, diabody, triabody, tetrabody, single-domain antigen binding fragments (sdAb, Nanobody), recombinant heavy-chain-only antibody (VHH), and other antibody fragments that maintain the binding specificity of the whole antibody, which may be more cost-effective to produce, more easily used, or more sensitive than the whole antibody. In some embodiments, the one, or two, or three, or more checkpoint inhibitors comprise at least one of atezolizumab, avelumab, durvalumab, ipilimumab, IPH4102, IPH43, IPH33, lirimumab, monalizumab, nivolumab, pembrolizumab, and their derivatives or functional equivalents. [000260] The combination therapies comprising the two types of derivative effector cells and one or more checkpoint inhibitors are applicable to treatment of liquid and solid cancers, including but not limited to cutaneous T-cell lymphoma, non-Hodgkin lymphoma (NHL), Mycosis fungoides, Pagetoid reticulosis, Sezary syndrome, Granulomatous slack skin, Lymphomatoid papulosis, Pityriasis lichenoides chronica, Pityriasis lichenoides et varioliformis acuta, CD30 + cutaneous T-cell lymphoma, Secondary cutaneous CD30 + large cell lymphoma, non-mycosis fungoides CD30 cutaneous large T-cell lymphoma, Pleomorphic T-cell lymphoma, Lennert lymphoma, subcutaneous T cell lymphoma, angiocentric lymphoma, blastic NK-cell lymphoma, B cell Lymphomas, hodgkins lymphoma (HL), Head and neck tumor; Squamous cell carcinoma, rhabdomyocarcoma, Lewis lung carcinoma (LLC), non-small cell lung cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, renal cell carcinoma (RCC), colorectal cancer (CRC), acute myeloid leukemia (AML), breast cancer, gastric cancer, prostatic small cell neuroendocrine carcinoma (SCNC), liver cancer, glioblastoma, liver cancer, oral squamous cell carcinoma, pancreatic cancer, thyroid papillary cancer, intrahepatic cholangiocellular carcinoma, hepatocellular carcinoma, bone cancer, metastasis, and nasopharyngeal carcinoma. [000261] In some embodiments, other than the two types of derivative effector cells as provided herein, a combination for therapeutic use further comprises one or more additional therapeutic agents comprising a chemotherapeutic agent or a radioactive moiety. As used herein, chemotherapeutic agent refers to cytotoxic antineoplastic agents, that is, chemical agents which preferentially kill neoplastic cells or disrupt the cell cycle of rapidly-proliferating cells, or which are found to eradicate stem cancer cells, and which are used therapeutically to prevent or reduce the growth of neoplastic cells. Chemotherapeutic agents are also sometimes referred to as antineoplastic or cytotoxic drugs or agents, and are well known in the art. [000262] In some embodiments, the chemotherapeutic agent comprises an anthracycline, an alkylating agent, an alkyl sulfonate, an aziridine, an ethylenimine, a methylmelamine, a nitrogen mustard, a nitrosourea, an antibiotic, an antimetabolite, a folic acid analog, a purine analog, a pyrimidine analog, an enzyme, a podophyllotoxin, a platinum-containing agent, an interferon, and an interleukin. Exemplary chemotherapeutic agents include, but are not limited to, alkylating agents (cyclophosphamide, mechlorethamine, mephalin, chlorambucil, heamethylmelamine, thiotepa, busulfan, carmustine, lomustine, semustine), animetabolites (methotrexate, fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, thioguanine, pentostatin), vinca alkaloids (vincristine, vinblastine, vindesine), epipodophyllotoxins (etoposide, etoposide orthoquinone, and teniposide), antibiotics (daunorubicin, doxorubicin, mitoxantrone, bisanthrene, actinomycin D, plicamycin, puromycin, and gramicidine D), paclitaxel, colchicine, cytochalasin B, emetine, maytansine, and amsacrine. Additional agents include aminglutethimide, cisplatin, carboplatin, mitomycin, altretamine, cyclophosphamide, lomustine (CCNU), carmustine (BCNU), irinotecan (CPT-11), alemtuzamab, altretamine, anastrozole, L- asparaginase, azacitidine, bevacizumab, bexarotene, bleomycin, bortezomib, busulfan, calusterone, capecitabine, celecoxib, cetuximab, cladribine, clofurabine, cytarabine, dacarbazine, denileukin diftitox, diethlstilbestrol, docetaxel, dromostanolone, epirubicin, erlotinib, estramustine, etoposide, ethinyl estradiol, exemestane, floxuridine, 5-flourouracil, fludarabine, flutamide, fulvestrant, gefitinib, gemcitabine, goserelin, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib, interferon alpha (2a, 2b), irinotecan, letrozole, leucovorin, leuprolide, levamisole, meclorethamine, megestrol, melphalin, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone, nofetumomab, oxaliplatin, paclitaxel, pamidronate, pemetrexed, pegademase, pegasparagase, pentostatin, pipobroman, plicamycin, polifeprosan, porfimer, procarbazine, quinacrine, rituximab, sargramostim, streptozocin, tamoxifen, temozolomide, teniposide, testolactone, thioguanine, thiotepa, topetecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinorelbine, and zoledronate. Other suitable agents are those that are approved for human use, including those that will be approved, as chemotherapeutics or radiotherapeutics, and known in the art. Such agents can be referenced through any of a number of standard physicians' and oncologists' references (e.g. Goodman & Gilman's The Pharmacological Basis of Therapeutics, Ninth Edition, McGraw-Hill, N.Y., 1995) or through the National Cancer Institute website (fda.gov/cder/cancer/druglistfrarne.htm), both as updated from time to time. [000263] In one embodiment, the combinational cell therapy comprises a therapeutic protein or peptide that is a CD3 engager and two populations of synthetic effector cells derived from genomically engineered iPSCs, wherein the derived synthetic NK or T cells comprise cell surface CD3 (cs-CD3). In some embodiments, the CD3 engager comprises one of blinatumomab, catumaxomab, ertumaxomab, RO6958688, AFM11, MT110/AMG 110, MT111/AMG211/MEDI-565, AMG330, MT112/BAY2010112, MOR209/ES414, MGD006/S80880, MGD007, and/or FBTA05. In yet some other embodiments, the CD3 engager comprises one of blinatumomab, catumaxomab, and ertumaxomab, and the derived NK or T cells comprise a CAR targeting CD19, BCMA, CD38, CD20, CD22, or CD123, hnCD16, and cs-CD3. In still some additional embodiments, the CD3 engager comprises one of blinatumomab, catumaxomab, and ertumaxomab, and the synthetic NK or T cells derived from genomically engineered iPSCs comprise cs-CD3, hnCD16, a CAR and one or more exogenous cytokine. [000264] Other than the two or more types of iPSC-derived hematopoietic lineage cells included in the therapeutic compositions, the compositions suitable for administration to a subject can further include one or more pharmaceutically acceptable carriers (additives) and/or diluents (e.g., pharmaceutically acceptable medium, for example, cell culture medium), or other pharmaceutically acceptable components. Pharmaceutically acceptable carriers and/or diluents are determined in part by the particular composition being administered, as well as by the particular method used to administer the therapeutic composition. Accordingly, there is a wide variety of suitable formulations of therapeutic compositions of the present invention (see, e.g., Remington's Pharmaceutical Sciences, 17 th ed.1985, the disclosure of which is hereby incorporated by reference in its entirety). [000265] These pharmaceutically acceptable carriers and/or diluents can be present in amounts sufficient to maintain a pH of the therapeutic composition of between about 3 and about 10. As such, a buffering agent can be as much as about 5% on a weight to weight basis of the total composition. Electrolytes such as, but not limited to, sodium chloride and potassium chloride can also be included in the therapeutic composition. In one aspect, the pH of the therapeutic composition is in the range from about 4 to about 10. Alternatively, the pH of the therapeutic composition is in the range from about 5 to about 9, from about 6 to about 9, or from about 6.5 to about 8. In another embodiment, the therapeutic composition includes a buffer having a pH in one of said pH ranges. In another embodiment, the therapeutic composition has a pH of about 7. Alternatively, the therapeutic composition has a pH in a range from about 6.8 to about 7.4. In still another embodiment, the therapeutic composition has a pH of about 7.4. [000266] The invention also provides, in part, the use of a pharmaceutically acceptable cell culture medium in particular compositions and/or cultures of the present invention. Such compositions are suitable for administration to human subjects. Generally speaking, any medium that supports the maintenance, growth, and/or health of the iPSC-derived effector cells in accordance with embodiments of the invention are suitable for use as a pharmaceutical cell culture medium. In particular embodiments, the pharmaceutically acceptable cell culture medium is a serum free, and/or feeder-free medium. In various embodiments, the serum-free medium is animal-free, and can optionally be protein-free. Optionally, the medium can contain biopharmaceutically acceptable recombinant proteins. Animal-free medium refers to medium wherein the components are derived from non-animal sources. Recombinant proteins replace native animal proteins in animal-free medium and the nutrients are obtained from synthetic, plant or microbial sources. Protein-free medium, in contrast, is defined as substantially free of protein. One having ordinary skill in the art would appreciate that the above examples of media are illustrative and in no way limit the formulation of media suitable for use in the present invention and that there are many suitable media known and available to those in the art. [000267] The iPSC-derived hematopoietic lineage cells can have at least 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99% T cells, NK cells, NKT cells, proT cells, proNK cells, CD34 + HE cells, HSCs, B cells, myeloid-derived suppressor cells (MDSCs), regulatory macrophages, regulatory dendritic cells, or mesenchymal stromal cells. In some embodiments, the iPSC- derived hematopoietic lineage cells have about 95% to about 100% T cells, NK cells, proT cells, proNK cells, CD34 + HE cells, or myeloid-derived suppressor cells (MDSCs). In some embodiments, the present invention provides therapeutic compositions having purified T cells or NK cells, such as a composition having an isolated population of about 95% T cells, NK cells, proT cells, proNK cells, CD34 + HE cells, or myeloid-derived suppressor cells (MDSCs) to treat a subject in need of the cell therapy. In a composition as provided herein comprising two or more types of synthetic effector cells derived from engineered iPSCs, the ratio of the two types of cells in cell count is between 100:1 and 1:100, or between 50:1 and 1:50, or between 20:1 to 1:20, or between 10:1 to 1:10, or between 2:1 to 1:2, or in any range in between. [000268] As a person of ordinary skill in the art would understand, both autologous and allogeneic hematopoietic lineage cells derived from iPSC based on the methods and compositions provided herein can be used in therapies utilizing combined cell types as described above. For autologous transplantation, the isolated populations of derived hematopoietic lineage cells are either complete or partial HLA-matched with the subject. In another embodiment, the derived hematopoietic lineage cells are not HLA-matched to the subject, wherein the derived hematopoietic lineage cells are NK cells or T cells with HLA-I and HLA-II null. [000269] In some embodiments, the number of each type of derived hematopoietic lineage cells in the composition is at least 0.1 x 10 5 cells, at least 1 x 10 5 cells, at least 5 x 10 5 cells, at least 1 x 10 6 cells, at least 5 x 10 6 cells, at least 1 x 10 7 cells, at least 5 x 10 7 cells, at least 1 x 10 8 cells, at least 5 x 10 8 cells, at least 1 x 10 9 cells, or at least 5 x 10 9 cells, per dose, with the cell count ratio of the two types of cells in between 100:1 and 1:100, 50:1 and 1:50, 20:1 to 1:20, 10:1 to 1:10, 2:1 to 1:2, 1:1, or any range in between. In some embodiments, the number of each type of derived hematopoietic lineage cells in the composition is about 0.1 x 10 5 cells to about 1 x 10 6 cells, per dose; about 0.5 x 10 6 cells to about 1 x 10 7 cells, per dose; about 0.5 x 10 7 cells to about 1 x 10 8 cells, per dose; about 0.5 x 10 8 cells to about 1 x 10 9 cells, per dose; about 1 x 10 9 cells to about 5 x 10 9 cells, per dose; about 0.5 x 10 9 cells to about 8 x 10 9 cells, per dose; about 3 x 10 9 cells to about 3 x 10 10 cells, per dose, with the cell count ratio of the two types of cells in between 100:1 and 1:100, 50:1 and 1:50, 20:1 to 1:20, 10:1 to 1:10, 2:1 to 1:2, 1:1, or any range in between. Generally, 1 x 10 8 cells/dose translates to 1.67 x 10 6 cells/kg for a 60 kg patient/subject. [000270] In one embodiment, the number of each type of the derived hematopoietic lineage cells in the composition is the number of immune cells in a partial or single cord of blood, or is at least 0.1 x 10 5 cells/kg of bodyweight, at least 0.5 x 10 5 cells/kg of bodyweight, at least 1 x 10 5 cells/kg of bodyweight, at least 5 x 10 5 cells/kg of bodyweight, at least 10 x 10 5 cells/kg of bodyweight, at least 0.75 x 10 6 cells/kg of bodyweight, at least 1.25 x 10 6 cells/kg of bodyweight, at least 1.5 x 10 6 cells/kg of bodyweight, at least 1.75 x 10 6 cells/kg of bodyweight, at least 2 x 10 6 cells/kg of bodyweight, at least 2.5 x 10 6 cells/kg of bodyweight, at least 3 x 10 6 cells/kg of bodyweight, at least 4 x 10 6 cells/kg of bodyweight, at least 5 x 10 6 cells/kg of bodyweight, at least 10 x 10 6 cells/kg of bodyweight, at least 15 x 10 6 cells/kg of bodyweight, at least 20 x 10 6 cells/kg of bodyweight, at least 25 x 10 6 cells/kg of bodyweight, at least 30 x 10 6 cells/kg of bodyweight, 1 x 10 8 cells/kg of bodyweight, 5 x 10 8 cells/kg of bodyweight, or 1 x 10 9 cells/kg of bodyweight, with the cell count ratio of the two types of cells in between 100:1 and 1:100, 50:1 and 1:50, 20:1 to 1:20, 10:1 to 1:10, 2:1 to 1:2, 1:1, or any range in between. [000271] In one embodiment, a dose of two types of derived hematopoietic lineage cells is delivered to a subject. In one illustrative embodiment, the effective amount of cells provided to a subject is at least 2 x 10 6 cells/kg, at least 3 x 10 6 cells/kg, at least 4 x 10 6 cells/kg, at least 5 x 10 6 cells/kg, at least 6 x 10 6 cells/kg, at least 7 x 10 6 cells/kg, at least 8 x 10 6 cells/kg, at least 9 x 10 6 cells/kg, or at least 10 x 10 6 cells/kg, or more cells/kg, including all intervening doses of cells, with the cell count ratio of the two types of cells in between 100:1 and 1:100, 50:1 and 1:50, 20:1 to 1:20, 10:1 to 1:10, 2:1 to 1:2, 1:1 or any range in between. [000272] In another illustrative embodiment, the effective amount of cells, with the cell count ratio of the two types of cells in between 100:1 and 1:100, 50:1 and 1:50, 20:1 to 1:20, 10:1 to 1:10, 2:1 to 1:2, 1:1 or any range in between, provided to a subject is about 2 x 10 6 cells/kg, about 3 x 10 6 cells/kg, about 4 x 10 6 cells/kg, about 5 x 10 6 cells/kg, about 6 x 10 6 cells/kg, about 7 x 10 6 cells/kg, about 8 x 10 6 cells/kg, about 9 x 10 6 cells/kg, or about 10 x 10 6 cells/kg, or more cells/kg, including all intervening doses of cells. [000273] In another illustrative embodiment, the effective amount of cells, with the cell count ratio of the two types of cells in between 100:1 and 1:100, 50:1 and 1:50, 20:1 to 1:20, 10:1 to 1:10, 2:1 to 1:2, 1:1 or any range in between, provided to a subject is from about 2 x 10 6 cells/kg to about 10 x 10 6 cells/kg, about 3 x 10 6 cells/kg to about 10 x 10 6 cells/kg, about 4 x 10 6 cells/kg to about 10 x 10 6 cells/kg, about 5 x 10 6 cells/kg to about 10 x 10 6 cells/kg, 2 x 10 6 cells/kg to about 6 x 10 6 cells/kg, 2 x 10 6 cells/kg to about 7 x 10 6 cells/kg, 2 x 10 6 cells/kg to about 8 x 10 6 cells/kg, 3 x 10 6 cells/kg to about 6 x 10 6 cells/kg, 3 x 10 6 cells/kg to about 7 x 10 6 cells/kg, 3 x 10 6 cells/kg to about 8 x 10 6 cells/kg, 4 x 10 6 cells/kg to about 6 x 10 6 cells/kg, 4 x 10 6 cells/kg to about 7 x 10 6 cells/kg, 4 x 10 6 cells/kg to about 8 x 10 6 cells/kg, 5 x 10 6 cells/kg to about 6 x 10 6 cells/kg, 5 x 10 6 cells/kg to about 7 x 10 6 cells/kg, 5 x 10 6 cells/kg to about 8 x 10 6 cells/kg, or 6 x 10 6 cells/kg to about 8 x 10 6 cells/kg, including all intervening doses of cells. [000274] In some embodiments, the therapeutic use of the composition comprising two or more types of derived hematopoietic lineage cells is a single-dose treatment, wherein the two or more types of cells are administered concurrently or consecutively. In some embodiments, the therapeutic use of the composition comprising two or more types of derived hematopoietic lineage cells is a multi-dose treatment. In some embodiments, the multi-dose treatment is one dose every day, every 3 days, every 7 days, every 10 days, every 15 days, every 20 days, every 25 days, every 30 days, every 35 days, every 40 days, every 45 days, or every 50 days, or any number of days in-between, with each dose of the two types of cells being administered concurrently or consecutively. [000275] In some embodiments, the compositions comprising two or more types of synthetic effector cells that are derived from engineered iPSC can be sterile, post-thaw, and can be suitable and ready for administration (i.e., can be administered without any further processing) to human patients/subjects. A cell-based composition that is ready for administration means that the composition does not require any further processing or manipulation prior to transplant or administration to a subject. In other embodiments, the invention provides two or more types of isolated populations of derived hematopoietic lineage cells that are expanded and/or modulated prior to administration with one or more agents including small chemical molecules. The modulation may be through contacting the derived hematopoietic lineage cells with a small chemical molecule, a protein, a nucleic acid, or a selected cell or a cell compotent thereof. The compositions and methods for modulating immune cells including iPSC-derived effector cells are described in greater detail, for example, in International Pub. No. WO2017/127755, the relevant disclosure of which is incorporated herein by reference. For derived hematopoietic lineage cells that genetically engineered to express recombinant TCR or CAR, the cells can be activated and expanded using methods as described, for example, in U.S. Patents 6,352,694. [000276] In certain embodiments, the primary stimulatory signal and the co- stimulatory signal for the derived hematopoietic lineage cells can be provided by different protocols. For example, the agents providing each signal can be in solution or coupled to a surface. When coupled to a surface, the agents can be coupled to the same surface (i.e., in "cis" formation) or to separate surfaces (i.e., in "trans" formation). Alternatively, one agent can be coupled to a surface and the other agent in solution. In one embodiment, the agent providing the co-stimulatory signal can be bound to a cell surface and the agent providing the primary activation signal is in solution or coupled to a surface. In certain embodiments, both agents can be in solution. In another embodiment, the agents can be in soluble form, and then cross-linked to a surface, such as a cell expressing Fc receptors or an antibody or other binding agent which will bind to the agents such as disclosed in U.S. Pub. Nos.2004/0101519 and 2006/0034810, the disclosures of which are incorporated by reference, for artificial antigen presenting cells (aAPCs) that are contemplated for use in activating and expanding T lymphocytes in embodiments of the present invention. [000277] Some variation in dosage, frequency, and protocol will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose, frequency and protocol for the individual subject. EXAMPLES [000278] The following examples are offered by way of illustration and not by way of limitation. EXAMPLE 1 – Materials and Methods [000279] To effectively select and test suicide systems under the control of various promoters in combination with different safe harbor loci integration strategies, a proprietary iPSC platform of the applicant was used, which enables single cell passaging and high- throughput, 96-well plate-based flow cytometry sorting, to allow for the derivation of clonal iPSCs with single or multiple genetic modulations. [000280] iPSC Maintenance in Small Molecule Culture: iPSCs were routinely passaged as single cells once confluency of the culture reached 75%–90%. For single-cell dissociation, iPSCs were washed once with PBS (Mediatech) and treated with Accutase (Millipore) for 3–5 min at 37°C followed with pipetting to ensure single-cell dissociation. The single-cell suspension was then mixed in equal volume with conventional medium, centrifuged at 225 × g for 4 min, resuspended in FMM, and plated on Matrigel-coated surface. Passages were typically 1:6–1:8, transferred tissue culture plates previously coated with Matrigel for 2–4 hr in 37°C and fed every 2–3 days with FMM. Cell cultures were maintained in a humidified incubator set at 37°C and 5% CO 2 . [000281] Human iPSC engineering with ZFN, CRISPR for targeted editing of modalities of interest: Using ROSA26 targeted insertion as an example, for ZFN mediated genome editing, 2 million iPSCs were transfected with a mixture of 2.5μg ZFN-L (FTV893), 2.5μg ZFN-R (FTV894) and 5ug donor construct, for AAVS1 targeted insertion. For CRISPR mediated genome editing, 2 million iPSCs were transfected with mixture of 5μg ROSA26-gRNA/Cas9 (FTV922) and 5ug donor construct, for ROSA26 targeted insertion. Transfection was done using Neon transfection system (Life Technologies) using parameters 1500V, 10ms, 3 pulses. On day 2 or 3 after transfection, transfection efficiency was measured using flow cytometry if the plasmids contain artificial promoter-driver GFP and/or RFP expression cassette. On day 4 after transfection, puromycin was added to the medium at concentration of 0.1ug/ml for the first 7 days and 0.2μg/ml after 7 days to select the targeted cells. During the puromycin selection, the cells were passaged onto fresh matrigel-coated wells on day 10. On day 16 or later of puromycin selection, the surviving cells were analyzed by flow cytometry for GFP + iPS cell percentage. [000282] Bulk sort and clonal sort of genome-edited iPSCs: iPSCs with genomic targeted editing using ZFN or CRISPR-Cas9 were bulk sorted and clonal sorted of GFP + SSEA4 + TRA181 + iPSCs after 20 days of puromycin selection. Single cell dissociated targeted iPSC pools were resuspended in chilled staining buffer containing Hanks' Balanced Salt Solution (MediaTech), 4% fetal bovine serum (Invitrogen), 1x penicillin/streptomycin (Mediatech) and 10 mM Hepes (Mediatech); made fresh for optimal performance. Conjugated primary antibodies, including SSEA4-PE, TRA181-Alexa Fluor-647 (BD Biosciences), were added to the cell solution and incubated on ice for 15 minutes. All antibodies were used at 7 μL in 100 μL staining buffer per million cells. The solution was washed once in staining buffer, spun down at 225 g for 4 minutes and resuspended in staining buffer containing 10 μM Thiazovivn and maintained on ice for flow cytometry sorting. Flow cytometry sorting was performed on FACS Aria II (BD Biosciences). For bulk sort, GFP + SSEA4 + TRA181 + cells were gated and sorted into 15ml canonical tubes filled with 7 ml FMM. For clonal sort, the sorted cells were directly ejected into 96-well plates using the 100 μM nozzle, at concentrations of 3 events per well. Each well was prefilled with 200 μL FMM supplemented with 5 μg/mL fibronectin and 1x penicillin/streptomycin (Mediatech) and previously coated overnight with 5x Matrigel.5x Matrigel precoating includes adding one aliquot of Matrigel into 5 mL of DMEM/F12, then incubated overnight at 4°C to allow for proper resuspension and finally added to 96-well plates at 50 μL per well followed by overnight incubation at 37°C. The 5x Matrigel is aspirated immediately before the addition of media to each well. Upon completion of the sort, 96-well plates were centrifuged for 1-2 min at 225 g prior to incubation. The plates were left undisturbed for seven days. On the seventh day, 150 μL of medium was removed from each well and replaced with 100 μL FMM. Wells were refed with an additional 100 μL FMM on day 10 post sort. Colony formation was detected as early as day 2 and most colonies were expanded between days 7-10 post sort. In the first passage, wells were washed with PBS and dissociated with 30 μL Accutase for approximately 10 min at 37°C. The need for extended Accutase treatment reflects the compactness of colonies that have sat idle in culture for prolonged duration. After cells are seen to be dissociating, 200 μL of FMM is added to each well and pipetted several times to break up the colony. The dissociated colony is transferred to another well of a 96-well plate previously coated with 5x Matrigel and then centrifuged for 2 min at 225 g prior to incubation. This 1:1 passage is conducted to spread out the early colony prior to expansion. Subsequent passages were done routinely with Accutase treatment for 3-5 min and expansion of 1:4-1:8 upon 75-90% confluency into larger wells previously coated with 1x Matrigel in FMM. Each clonal cell line was analyzed for GFP fluorescence level and TRA1-81 expression level. Clonal lines with near 100% GFP + and TRA1-81 + were selected for further PCR screening and analysis. Flow cytometry analysis was performed on Guava EasyCyte 8 HT (Millipore) and analyzed using Flowjo (FlowJo, LLC). EXAMPLE 2 – Enhanced Derivative NK and T Effector Cells [000283] Derivative NK cells from CAR-expressing iPSCs were obtained according to the directed differentiation platform described herein. NK cell maturation was enhanced in the synthetic hnCD16-CAR-IL-15/IL-15Ra iNK cells, as demonstrated by increased production of granzyme B associated with NK killing ability and increased expression of KIR2DL3 and KIR2DL1, conferring licensing status for the NK cells to acquire effector functions. In vitro cytotoxicity of hnCD16-CAR-IL15/IL15Ra iNK cells against Nalm6 and ARH-77 target cell lines were investigated, which showed CAR directed CD19 specific killing and rituximab- induced ADCC against B cell malignancies in vitro. [000284] Peripheral blood derived T cells with targeted insertion of a CD19 CAR into the T cell receptor α (TRAC) locus under the transcriptional control of its endogenous regulatory elements were reprogrammed to generate a single cell-derived clonal TRAC-targeted CAR containing master iPSC line (TRAC-CAR TiPSC). At around day 28 of T cell differentiation, the derived cells were able to grow and expand further in suspension in the absence of TCR expression. This synthetic T cell (TRAC-CAR iT) demonstrated in vitro functional capability of eliciting an efficient cytotoxic T lymphocyte response to CD19 antigen challenge with production of effector cytokines (IFNγ, TNFα, IL2), degranulation (CD107a/b, Perforin, Granzyme B), proliferation (>85% entry into cell cycle) and upregulation of activation markers CD69 and CD25. The production of IFNγ and TNFα by mature TRAC-CAR iT cells is markedly higher than primary T cells expressing CAR. The TRAC-CAR iT also targets tumor in an antigen specific manner, and without variability in antigen specific cytotoxicity seen in primary T cells expressing CAR. [000285] It is further shown here that the mature iNK cells obtained through directed differentiation of iPSCs contain longer telomeres compared to adult peripheral blood NK cells. Telomere length was determined by flow cytometry for iPSC, adult peripheral blood NK cells, and iPSC-derived NK cells using the 1301 T cell leukemia line as a control (100%) with correction for the DNA index of G0/1 cells. As shown in Figure 2, iPSC-derived NK cells maintain significantly longer telomere length when compared to adult peripheral blood NK cells (p=.105, ANOVA), representing greater proliferation, survival and persistence potential in the iPSC-derived NK cells. Similar observation of longer telomere lengthening is also in iPSC- derived T cells. This is consistent with the fact that telomere shortening occurs with cellular aging and is associated with stem cell dysfunction and cellular senescence. EXAMPLE 3 – Combination of effector cell types results in durable response over multiple rounds of cytotoxicity and multi-antigen targeting [000286] Raji tumor cells were pre-plated followed by addition of CAR-iT (0.3:1 E:T, o/n), and the subsequent addition either of 0.1μg/ml RTX (Rituximab), or CAR-iNK and 0.1ug/ml RTX (0.3:1 E:T ratio) for a total duration of 96 hours. As shown in Figure 3, the addition of CAR-iNK improves cytotoxicity of CAR-iT, which is augmented further by ADCC. [000287] In another assay, the Raji-parental targets (Figure 4A) and Raji-CD19KO targets (Figure 4B) were immobilized on the surface of 96 well plates. Targets were pre-cultured as a single type of each, or in a 50/50 combination co-culture to resemble duo targeting mix. As shown in Figure 4, CAR-iT, CAR-iNK in combination were added in increased E:T ratios, and the combination of the cell products was shown to enable cytotoxicity/targeting in a CD19 antigen escape setting (Figure 4B), and the further addition of RTX enabled the effect of direct cytotoxicity through ADCC (Figure 4A and 4B) resulting in enhanced target elimination. EXAMPLE 4 – Combination of effector cell types with mAb increases efficacy in diverse B cell malignancies [000288] Combinations of CAR-iT, CAR-iNK and rituximab were tested against a panel of different tumor cell lines representing B cell malignancies, as well as a primary B cell line transformed with Epstein Barr Virus (EBV), such as the ARH-77 cell line. Figure 5A shows increases in anti-tumor activity with CAR-iT alone, CAR-iT and CAR-iNK, and CAR-iT and CAR-iNK in combination with Rituximab (0.1μg/mL) under the titration of effector to target ratios against target cell line ARH-77 (CD19 + CD20 + ). As shown, the combination of both CAR- iT and CAR-iNK in addition to RTX has the highest cytotoxicity. [000289] Relative activity of CAR-iT, CAR-iNK and rituximab versus a panel of diverse B tumor lines is calculated as area under the curve (AUC) and pictured in the heatmap shown in Figure 5B. Nalm-6 (CD19 + , CD20-) was used as a control to confirm CD19 specificity. As shown in Figure 5B, the reactivity and the breadth of reactivity across the diverse B cell malignancies increases with the successive addition of CAR-iT alone, CAR-iT and CAR-iNK, and CAR-iT and CAR-iNK in combination with Rituximab (0.1μg/mL). [000290] An in vivo lymphoma model using NSG mice inoculated with RAJI tumor cells shows that treatment of mice with Rituximab alone (3 doses of 3μg/mouse over 7 days) was partially effective (Figures 6A and 6D). Treatment of mice with primary CAR-T cells was more effective than Rituximab alone (Figures 6B and 6D). A combination of CAR-iT, CAR-iNK and Rituximab proved the most effective in clearing Raji tumor cells over a period of 41 days (Figures 6C and 6D). EXAMPLE 5 – Combination of effector cell types and checkpoint inhibitor antagonists [000291] Checkpoints are cell molecules, often cell surface molecules, capable of suppressing or downregulating immune responses when not inhibited. Checkpoint inhibitors are antagonists capable of reducing checkpoint gene expression or gene products, or deceasing activity of checkpoint molecules. The development of checkpoint inhibitors (CI) targeting PD1/PDL1 or CTLA4 has transformed the oncology landscape, with these agents providing long term remissions in multiple indications. However, many tumor subtypes are resistant to checkpoint blockade therapy, and relapse remains a significant concern. Therefore, novel therapeutic approaches with the ability to overcome CI resistance are needed. [000292] Assays are designed to show whether the derivative NK cells have the ability to both recruit the derivative T cells to the tumor microenvironment (TME) and augment derivative T cell activation at the tumor site. Migration of activated derivative T cells is demonstrated upon secretion of CCL3, CCL4, CXCL10 and other soluble factors by activated derivative NK cells. In this assay, hnCD16 iNK cells are combined with either SKOV-3 or SKOV-3-PDL1 expressing high levels of PDL1 in the presence of an ADCC-inducing anti-PDL1 antibody. After overnight incubation, supernatants are collected and incubated in the lower chamber of a standard transwell chemotaxis chamber with derivative T cells in the upper chamber for 24 hours. After incubation, derivative T cell migration to the lower chamber is quantified by flow cytometry to determine whether activated iNK column cells enhance derivative T cell migration. [000293] It was previously shown that upon activation, the derivative NK cells exhibit direct antitumor capacity evidenced by the cells’ production of copious inflammatory cytokines and chemokines, including interferon gammas (IFNγ), CCL3, CCL4, CXCL10, and CCL22. IFNγ plays a critical role in regulating anti-tumor T cell activity. In an in vivo assay, NSG mice are injected with 1E7 iNK cells I.P. (intraperitoneal), or 5E6 activated derivative T cells R.O. (retro- orbital), or both. Four days later, the peripheral blood and peritoneal cavity are assessed for the presence of derivative T cells by flow cytometry. Compared with mice receiving derivative T cells but no derivative NK cells, mice that received iPSC-derived NK cells I.P. were expected to have reduced derivative T cell frequency in peripheral blood and increased derivative T cells in the peritoneal cavity due to the derivative NK cells’ ability to enhance derivative T cell migration by recruiting activated derivative T cells out of the circulation and into the peritoneum. [000294] Utilizing an in vitro three-dimensional tumor spheroid model, enhanced infiltration of derivative T cells into tumor spheroids in the presence of the derivative NK cells is observed. 30,000 derivative T cells that are green fluorescently labelled are either incubated alone with SKOV-3 microspheres (red nuclei) or in combination with 15,000 iNK cells and imaged for more than 15 hours. It is expected that derivative T cells alone fail to penetrate the center of the spheroid, but addition of iNK cells promotes derivative T cell infiltration to tumor spheroid and tumor spheroid destruction. [000295] The enhanced derivative T cell infiltration of tumor spheroids and enhanced cytotoxicity when co-cultured with derived NK cells are also shown quantitatively by measuring total integrated green fluorescence intensity within the largest red object mask. Infiltration of derivative T cells into SKOV-3 spheroids is measured for 24 hours of co-culture with derived NK cells (1:1 ratio), CD3 + T cells (2:1 ratio), or iNK (1:1 ratio) + iT cells (2:1 ratio), to show that derived NK cells enhance derivative T cell infiltration of the tumor spheroids. [000296] Co-culture of derivative T cells and derivative NK cells in a 3D tumor spheroid model leads to tumor cell killing and enhanced production of IFNγ and TNFα. After 7 days of derived NK cell incubation with SKOV-3 spheroids in 1:1 ET ratio, CD3 + T cells (2:1 ratio), or iNK (1:1 ratio) + iT cells (2:1 ratio)), supernatants are collected and assessed for TNFα and IFNγ production. iPSC-derived NK cells synergize with derivative T cells in enhancing production of IFNγ and TNFα for solid tumor killing in a spheroid model when co-culture of iT cells with iPSC-NK and led to increased cytokine production for both CD4 + and CD8 + iT cells. [000297] As such, by promoting recruitment of derivative T cells to the tumor site and by enhancing derivative T cell activation and infiltration, these functionally potent derivative NK cells are evidenced to be capable of synergizing with derivative T cell targeted immunotherapies, including the checkpoint inhibitors, to relieve local immunosuppression and to reduce tumor burden in a solid tumor setting. Together, these data provide evidence supporting an allogenic combination therapy comprising derivative NK cells and derivative T cells, optionally further in combination with a checkpoint inhibitor or other T cell targeted therapeutic agents. [000298] Suitable checkpoint inhibitors for a combinational therapy with the derivative NK and derivative T cell combo are disclosed herein. [000299] The combination therapies comprising the derivative NK and derivative T cell and optionally one or more checkpoint inhibitors are applicable to treatment of liquid and solid cancers. When evaluating responsiveness to the combination therapy comprising the provided derivative NK and derivative T cell combo and anti-immune checkpoint inhibitor(s), the response can be measured by criteria comprising at least one of: clinical benefit rate, survival until mortality, pathological complete response, semi-quantitative measures of pathologic response, clinical complete remission, clinical partial remission, clinical stable disease, recurrence-free survival, metastasis free survival, disease free survival, circulating tumor cell decrease, circulating marker response, and RECIST (Response Evaluation Criteria In Solid Tumors) criteria. [000300] One skilled in the art would readily appreciate that the methods, compositions, and products described herein are representative of exemplary embodiments, and not intended as limitations on the scope of the invention. It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the present disclosure disclosed herein without departing from the scope and spirit of the invention. [000301] All patents and publications mentioned in the specification are indicative of the levels of those skilled in the art to which the present disclosure pertains. All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated as incorporated by reference. [000302] The present disclosure illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations that are not specifically disclosed herein. Thus, for example, in each instance herein any of the terms “comprising,” “consisting essentially of,” and “consisting of” may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the present disclosure claimed. Thus, it should be understood that although the present disclosure has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.