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1. WO2020142694 - ERO1-ALPHA INHIBITORS

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[ EN ]

WHAT IS CLAIMED IS:

1. A reaction mixture comprising a population of immune effector cells, wherein a plurality of the cells of the population in the reaction mixture have a reduced expression of EROla.

2. A reaction mixture comprising a population of immune effector cells, wherein a plurality of the cells of the population in the reaction mixture comprise a vector comprising a nucleic acid sequence encoding a protein which knocks out EROla.

3. The reaction mixture of claim 2, wherein the vector is a DNA, RNA, plasmid, lentivirus vector, adenoviral vector, or retrovirus vector.

4. A reaction mixture comprising a population of immune effector cells, wherein a plurality of the cells of the population in the reaction mixture comprise a nucleic acid molecule that comprises a sequence which knocks out EROla.

5. A reaction mixture of any one of claims 1-4, wherein the immune effector cells are T cells.

6. A reaction mixture of any one of claims 1-5, comprising a population of immune effector cells containing less than 50%, 40%, 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2% 1% of EROla expressing T cells.

7. A method of treating cancer in a subject comprising administering the reaction mixture of any one of claims 1-6 to the subject in need thereof.

8. A method of treating a cancer in a subject, comprising administering modified T cells to said subject in need thereof wherein said modified T cells comprise T cells in which expression of EROla is reduced or eliminated.

9. The method of claim 7 or 8, wherein the cancer is sarcoma, melanoma, lung cancer, adenocarcinoma, metastatic bone disease or a solid tumor.

10. The method of any one of claims 7-9, further comprising administering the modified T cells locally to one or more tumors and/or tumor microenvironments of the individual.

11. The method of any one of claims 7-10, further comprising systemically delivering the modified T cells to the subject.

12. A method of making a modified population of immune effector cells, comprising

a. obtaining a population of immune effector cells,

b. modifying a plurality of the immune effector cells within the population to eliminate or reduce expression of EROla thereby creating a modified population of immune effector cells.

13. The method of claim 12, wherein the immune effector cells are T cells.

14. The method of claim 12 or 13, wherein the method further provides contacting the

plurality of the immune effector cells with CRIPR/Cas9 genes that silence or knock out expression of EROla.

15. The method of any one of claims 12-14, wherein the population of immune effector cells or the modified population of immune effector cells are contacted with a EROla inhibitor.

16. The method of claim 15, wherein the EROla inhibitor is EROl Inhibitor II (EN460).

17. The method of any one of claims 12-16, wherein the population of immune effector cells or the modified population of immune effector cells are contacted with N-acetyl cysteine (NAC).

18. The method of any one of claims 12-17, wherein the population of the modified immune effector cells is expanded for a period of 8 days or less, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day or less..

19. The method of any one of claims 12-18, wherein the population of immune effector cells are obtained from a subject afflicted with cancer.

20. The method of claim 19, wherein the cancer is a sarcoma or a tumor.

21. The method of any one of claims 12-20, wherein the population of cells is cryopreserved after the appropriate expansion period.

22. The method of any one of claims 7-11 and 19-21, wherein the subject is a human.

23. A method for treating a cancer in a mammal, comprising administering to said mammal an EROla inhibitor.

24. The method of claim 23, wherein the EROla inhibitor reduces or eliminates the

expression of EROla.

25. The method of any one of claims 7-11 and 19-24, further comprising administering a checkpoint inhibitor.

26. The method of claim 25, wherein the checkpoint inhibitor is ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab-rwlc.

27. The method of claim 25, wherein the checkpoint inhibitor is an programmed cell death protein 1 (PD-1) antagonist or a T-lymphocyte-associated protein 4 (CTLA-4) antagonist.

28. The method according to claim 27, wherein the PD-1 or CTLA-4 antagonist is:

a. an antibody, or antigen binding fragment of an antibody, that specifically binds to, and inhibits activation of, an PD-1 or CTLA-4 receptor, or

b. a soluble form of an PD-1 or CTLA-4 receptor that specifically binds to a PD-1 or CTLA-4 ligand and inhibits the PD-1 or CTLA-4 ligand from binding to the PD-1 or CTLA-4 receptor.

29. The method according to claim 27, wherein the PD-1 ligand is PD-L1 or PD-L2.

30. The method according to claim 27, wherein the PD-1 antagonist is a PD-1 monoclonal antibody.

31. The method of claim 27, wherein the PD-1 antagonist is nivolumab, pembrolizumab, avelumab, durvalumab, cemiplimab, or atezolizumab.

32. The method of claim 27, wherein the CTLA-4 antagonist is ipilimumab or

tremelimumab.

33. The method according to any one of claims 25-32, wherein the administration of the

modified T cells or the EROla inhibitor precedes the administration of the checkpoint inhibitor.

34. The method according to any one of claims 25-32, wherein the administration of the

checkpoint inhibitor precedes the administration of the modified T cells or the EROla inhibitor.

35. The method according to any one of claims 25-32, wherein the modified T cells or the EROla inhibitor is administered adjunctively to the checkpoint inhibitor.

36. The method according to any one of claims 25-32, wherein the checkpoint inhibitor is administered adjunctively to the modified T cells or the EROla inhibitor.

37. The method of any one of claims 25-36, wherein the checkpoint inhibitor is administered daily, more often than once daily or less often than once daily.

38. The method according to claim 37, wherein the checkpoint inhibitor is administered once every 3 days, once every week, once every 2 weeks, once every 3 weeks or once every 4 weeks.

39. The method according to any one of claims 27-36, wherein the PD-1 antagonist is nivolumab and the amount of the nivolumab administered to the subject is 3 mg/kg body weight every 3 weeks, 240 mg every 2 weeks or 480 mg every 4 weeks.

40. The method according to any one of claims 27-36, wherein the PD-1 antagonist is

pembrolizumab and the amount of the pembrolizumab administered to the subject is 200 mg every 3 weeks.

41. The method according to any one of claims 27-36, wherein the PD-1 antagonist is

avelumab and the amount of the avelumab administered to the subject is 800 mg every 2 weeks.

42. The method according to any one of claims 27-36, wherein the PD-1 antagonist is

durvalumab and the amount of the durvalumab administered to the subject is 10 mg/kg body weight every 2 weeks.

43. The method according to any one of claims 27-36, wherein the PD-1 antagonist is

cemiplimab and the amount of the cemiplimab administered to the subject is 250 mg every 3 weeks.

44. The method according to any one of claims 27-36, wherein the PD-1 antagonist is

atezolizumab and the amount of the atezolizumab administered to the subject is 840 mg every 2 weeks, 1200 mg every 3 weeks or 1680 mg every 4 weeks.

45. The method according to any one of claims 25-44, wherein the subject is receiving

checkpoint inhibitor therapy prior to initiating modified T cells therapy or EROla inhibitor therapy.

46. The method according to any one of claims 25-44, wherein the subject is receiving

modified T cells therapy or EROla inhibitor therapy prior to initiating checkpoint inhibitor therapy.

47. The method according to any one of claims 25-46, where in the subject is receiving a first therapy for at least 8 weeks, at least 10 weeks, at least 24 weeks, at least 28 weeks, at least 48 weeks or at least 52 weeks prior to initiating a second therapy.

48. The method according to any one of claims 25-47, wherein periodic administration of the modified T cells and/or EROla inhibitor and/or the checkpoint inhibitor continues for at least 3 days, for at least 30 days, for at least 42 days, for at least 8 weeks, for at least 12 weeks, for at least 24 weeks or for at least 6 months.

49. The method according to any one of claims 25-48, wherein each of the amount of the modified T cells or EROla inhibitor when taken alone, and the amount of the checkpoint inhibitor when taken alone is effective to treat the subject.

50. The method according to any one of claims 25-48, wherein either the amount of the

modified T cells or the EROla inhibitor when taken alone, the amount of the checkpoint inhibitor when taken alone, or each such amount when taken alone is not effective to treat the subject.

51. The method according to any one of claims 25-48, wherein either the amount of the

modified T cells or the EROla inhibitor when taken alone, the amount of the checkpoint inhibitor when taken alone, or each such amount when taken alone is less effective to treat the subject.

52. The method of any one of claims 23-51, wherein the EROla inhibitor is EROl Inhibitor II (EN460).

53. The method according to any one of claims 23-52, wherein the subject or mammal is a human patient.

54. A EROla inhibitor for use as an add-on therapy or in combination with a checkpoint inhibitor in treating a subject afflicted with cancer.

55. A checkpoint inhibitor for use as an add-on therapy or in combination with an EROla inhibitor in treating a subject afflicted with cancer.

56. Use of an amount of a checkpoint inhibitor and an amount of an EROla inhibitor in the preparation of a combination for treating a subject afflicted with cancer wherein the checkpoint inhibitor and the EROla inhibitor are prepared to be administered

simultaneously, contemporaneously or concomitantly.

57. A combination of EROla inhibitor and an checkpoint inhibitor for use in the manufacture of a medicament.

58. The combination according to claim 57, wherein the medicament is for the treatment, prevention, or alleviation of a symptom of cancer.