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1. (WO2018089423) CD38-NAD+ REGULATED METABOLIC AXIS IN ANTI-TUMOR IMMUNOTHERAPY
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WHAT IS CLAIMED IS:

1. An ex vivo method for producing hybrid Th1/Th17 cells comprising:

(a) obtaining a starting population of T cells; and

(b) culturing the starting population of T cells in the presence of IL6, IL1 β, IL23, TGFβ and IL-12, thereby differentiating the starting population of T cells to hybrid Th1/Th17 cells.

2. The method of claim 1, wherein the TGFβ is present at a concentration of 0.1 to 0.5 ng/mL.

3. The method of claim 1, wherein the IL1β, IL23, IL6, and/or IL12 are present at a concentration of about 5 to 30 ng/mL.

4. The method of claim 1, wherein the culture further comprises anti-CD3 and anti-CD28.

5. The method of claim 4, wherein the anti-CD3 and anti-CD28 are bound to a surface.

6. The method of claim 1, wherein the culture does not comprise IL-2.

7. The method of claim 1, wherein the culturing is for 2 to 5 days.

8. The method of claim 1, wherein the culture further comprises anti-IL4 and/or anti-IFNα.

9. The method of claim 1, wherein the starting population of T cells are CD4+ T cells.

10. The method of claim 9, wherein the CD4+ T cells are isolated from splenocytes.

11. The method of claim 1, wherein the starting population of T cells are human T cells.

12. The method of claim 1, wherein the isolation is performed by magnetic-bead sorting or fluorescence-activated cell sorting.

13. The method of claim 1, wherein the hybrid Th1/Th17 cells have an effector and stemness phenotype.

14. The method of claim 1, wherein the hybrid cells have increased NAD+ as compared to Th17 cells.

15. The method of claim 14, wherein the increase is at least 10-fold.

16. The method of claim 14, wherein the increase is at least 30-fold.

17. The method of claim 1, wherein the hybrid Th1/Th17 cells have reduced expression of CD38 as compared to Th1 or Th17 cells.

18. The method of claim 1, wherein the hybrid Th1/Th17 cells have at least two-fold higher Sirt1 activity as compared to Th17 cells.

19. The method of claim 1, wherein the hybrid Th1/Th17 cells co-express elevated levels of IFN γ and IL17.

20. The method of claim 1, wherein the hybrid Th1/Th17 cells express transcription factors T-bet, RORγ, and/or IRF-4.

21. The method of claim 1, wherein the hybrid Th1/Th17 cells express chemokine receptors CXCR3 and/or CCR6.

22. The method of claim 1, wherein the hybrid Th1/Th17 cells express effector genes GzmB, Tbx21, and/or GM-CSF.

23. The method of claim 1, wherein the hybrid Th1/Th17 cells express stemness genes IL22, IL23R, TCF7, BCL6, and/or β-catenin.

24. The method of claim 1, wherein the hybrid Th1/Th17 cells exhibit increased anti-tumor activity as compared to Th1 or Th17 cells.

25. A pharmaceutical composition comprising the hybrid Th1/Th17 cells with low or essentially no expression of CD38 and a pharmaceutical carrier.

26. The composition of claim 25, wherein the hybrid Th1/Th17 cells are produced according to any one of the claims 1-24.

27. A composition comprising an effective amount of hybrid Th1/Th17 cells with low or no expression of CD38 for the treatment of cancer in a subject.

28. The composition of claim 26, wherein the hybrid Th1/Th17 cells are produced according to any one of the claims 1-24.

29. A method of treating cancer comprising (a) administering an effective amount of T cells with low or no expression of CD38 and/or (b) administering anti-CD38 antibody in combination with an effective amount of T cells to the subject.

30. The method of claim 29, wherein the T cells with low or no expression of CD38 are the hybrid Th1/Th17 cells produced according to any one of claims 1-24.

31. The method of claim 29, wherein the T cells with low or no expression of CD38 are produced by activating T cells in the presence of an anti-CD38 antibody.

32. The method of claim 29, wherein the T cells with low or no expression of CD38 are produced by contacting the T cells with siRNA or shRNA.

33. The method of claim 29, wherein the T cells with low or no expression of CD38 are produced by genetically modifying the T cells.

34. The method of claim 33, wherein genetically modifying comprises the use of TALENs or the CRISPR/Cas9 system.

35. The method of claim 29, wherein the T cells of (b) are unprogrammed Th0 cells.

36. The method of claim 29, wherein the cancer is lung cancer, melanoma, or prostate cancer.

37. The method of claim 29, wherein the T cells are antigen-specific T cells.

38. The method of claim 37, wherein the T cells are genetically modified to express a recombinant T cell receptor (TCR) or chimeric antigen receptor (CAR) comprising an intracellular signaling domain, a transmembrane domain, and an extracellular domain comprising an antigen binding region.

39. The method of claim 37 or 38, wherein the antigen is a tumor-associated antigen. 40. The method of claim 29, wherein the anti-CD38 antibody or antigen-binding fragment thereof is a monoclonal antibody, a chimeric antibody, a CDR- grafted antibody, a humanized antibody, a Fab, a Fab', a F(ab')2, a Fv, or a scFv.

41. The method of claim 29, further comprising administering an immune checkpoint inhibitor.

42. The method of claim 41, wherein the immune checkpoint inhibitor is an anti-PD1 antibody and/or an anti-CTLA antibody.

43. The method of claim 42, wherein the at least one checkpoint inhibitor is selected from an inhibitor of CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, BTLA, B7H3, B7H4, TIM3, KIR, or A2aR.

44. The method of claim 42, wherein the PD-1 binding antagonist is nivolumab, pembrolizumab, pidillizumab, AMP-514, REGN2810, CT-011, BMS 936559, MPDL328OA or AMP-224.

45. The method of claim 42, wherein the anti-CTLA-4 antibody is tremelimumab or ipilimumab.

46. The method of claim 29, further comprising administering at least a second therapeutic therapy.

47. The method of claim 46, wherein the at least a second therapeutic agent comprises chemotherapy, immunotherapy, surgery, radiotherapy, or biotherapy.

48. The method of claim 46, wherein the T cells and/or the at least a second therapeutic agent are administered intravenously, intraperitoneally, intratracheally, intratumorally, intramuscularly, endoscopically, intralesionally, percutaneously, subcutaneously, regionally, or by direct injection or perfusion.

49. The method of claim 46, wherein the T cells are administered prior to or after the at least a second therapeutic agent.

50. The method of claim 46, wherein the T cells are administered simultaneously with the at least a second therapeutic agent.

51. The method of claim 29, wherein the subject is human.