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1. WO2020112815 - ANTI-LMP2 TCR-T CELL THERAPY FOR THE TREATMENT OF EBV-ASSOCIATED CANCERS

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[ EN ]

CLAIMS

We claim:

1. A population of T-cells comprising an engineered T-cell receptor (TCR), wherein the engineered TCR activates T-cells in response to a Latent membrane protein 2 (LMP2) antigen.

2. The population of T-cells of claim 1, wherein the engineered TCR comprises the amino acid sequence of SEQ ID NO:03.

3. The population of T-cells of claim 1 , wherein the engineered TCR comprises the amino acid sequence of SEQ ID NO:09.

4. The population of T-cells of any of claims 1-3, wherein the LMP2 antigen comprises the sequence of SSCSSCPLSK (SEQ ID NO:01).

5. The population of T-cells of any of claims 1 -4, wherein the population of T-cells comprises a therapeutically effective amount of cells for the treatment of a cancer comprising LMP2 in a subject.

6. The population of T-cells of any of claims 1-5, wherein the subject expresses human leukocyte antigen subtype A11 (HLA-A11).

7. The population of T-cells of any of claims 1-6, wherein at least a portion of the population of T-cells produces or has the potential to produce one or more cytokines.

8. The population of T-cells of claim 7, wherein the one or more cytokines are selected from the group consisting of IL-2, IFN-gamma, TNF -alpha, Granzyme A, Granzyme B, and GM-CSF.

9. The population of T-cells of any of claims 6-8, wherein the cancer is selected from the group consisting of nasopharyngeal carcinoma (NPC), lymphoma, gastric cancer, lung cancer, melanoma, breast cancer, prostate cancer, colon cancer, renal cell carcinoma, ovarian cancer, neuroblastoma, rhabdomyosarcoma, and leukemia.

10. The population of T-cells of claim 9, wherein the cancer is an EBV -associated cancer.

11. The population of T-cells of claim 9, wherein the cancer is nasopharyngeal carcinoma (NPC).

12. The population of T-cells of claim 9, wherein the cancer is lymphoma.

13. The population of T-cells of claim 9, wherein the cancer is gastric cancer.

14. A pharmaceutical composition, wherein the composition comprises the population of T-cells according to any of claims 1-13, and a pharmaceutically acceptable carrier.

15. The pharmaceutical composition of claim 14, wherein the pharmaceutically acceptable carrier supports maintenance of a therapeutically effective amount of cells for the treatment of a cancer comprising LMP2.

16. The pharmaceutical composition of claim 14 or 15, further comprising at least one therapeutic agent.

17. A method of treating a subject suffering from a cancer comprising LMP2, wherein the method comprises administering to the subject a therapeutically effective amount of the population of T-cells of any of claims 1-13, or the pharmaceutical composition of any of claims 14-16, wherein the administration induces an anti-tumor response to the cancer.

18. The method of claim 17, wherein the cancer is selected from group consisting of nasopharyngeal carcinoma (NPC), lymphoma, gastric cancer, lung cancer, melanoma, breast cancer, prostate cancer, colon cancer, renal cell carcinoma, ovarian cancer, neuroblastoma, rhabdomyosarcoma, and leukemia.

19. The method of claim 18, wherein the cancer is an EBV -associated cancer.

20. The method of claim 18, wherein the cancer is nasopharyngeal carcinoma (NPC).

21. The method of claim 18, wherein the cancer is lymphoma.

22. The method of claim 18, wherein the cancer is gastric cancer.

23. The method of any of claims 17-22, wherein the anti-tumor response results in a reduction of tumor volume by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%.

24. An isolated nucleic acid comprising a polynucleotide encoding an engineered TCR comprising the amino acid sequence of SEQ ID NO:03.

25. The isolated nucleic acid of claim 24, wherein the polynucleotide comprises the nucleic acid sequence of SEQ ID NO:08.

26. A vector comprising the nucleic acid of claim 25.

27. An isolated nucleic acid comprising a polynucleotide encoding an engineered TCR comprising the amino acid sequence of SEQ ID NO:09.

28. The isolated nucleic acid of claim 27, wherein the polynucleotide comprises the nucleic acid sequence of SEQ ID NO: 14.

29. A vector comprising the nucleic acid of claim 28.

30. The vector of claim 26 or claim 29, wherein the vector is selected from the group consisting of plasmids, cosmids, artificial chromosomes (such as a yeast artificial chromosome (YAC) or a bacterial artificial chromosome (BAC)), and viruses (such as a retrovirus, a lenti virus, an adenovirus, an adeno-associated virus (AAV), and a herpesvirus).

31. A method of preparing a population of T-cells, wherein the method comprises:

(1) transfecting or transducing isolated T-cells with the isolated nucleic acid of claims 24 or 27 or the vector of claim 26 or 29; and

(2) expanding the T-cells following transfection or transduction, wherein the T-cells are expanded by culturing in the presence of anti-CD3, anti-CD3/anti-CD28, or LMP protein presented by artificial APCs.

32. The method of claim 31 , wherein the isolated T-cells are isolated from a human.

33. The method of claim 32, wherein the human is a subject suffering from a cancer comprising LMP2.

34. The method of any of claims 31-33, wherein the subject suffering from the cancer comprising LMP2 expresses human leukocyte antigen subtype All (HLA-A11).

35. A method of inhibiting the growth of a tumor comprising a Latent membrane protein

2 (LMP2) antigen in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a population of T-cells comprising an engineered T cell receptor (TCR) with a TCR alpha chain having the sequence of SEQ ID NO: 4 or 10, and a TCR beta chain having the sequence of SEQ ID NO: 6 or 12, and wherein the growth of the tumor comprising tire LMP2 antigen is inhibited.

36. The method of claim 35, wherein the tumor comprises a human leukocyte antigen subtype All (HLA-A11).

37. The method of claim 35, wherein the tumor is from an EBV-associated cancer.

38. The method of claim 35 or 36, wherein the cancer is nasopharyngeal carcinoma, lymphoma, or gastric cancer.

39. The method of any of claims 35-38, wherein the engineered TCR comprises the TCR alpha chain of SEQ ID NO: 4, and the TCR beta chain of SEQ ID NO:6.

40. The method of claim 39, wherein the TCR alpha chain comprises a CDR3 alpha comprising the sequence AWNNNDMRFG (SEQ ID NO:5), and the TCR beta chain comprises a CDR3 beta comprising the sequence of ASSPGRWYEQF (SEQ ID NO:7).

41. The method of any of claims 35-38, wherein the engineered TCR comprises the TCR alpha chain of SEQ ID NO: 10, and the TCR beta chain of SEQ ID NO: 12.

42. The method of claim 41 , wherein the TCR alpha chain comprises a CDR3 alpha comprising the sequence AVLNNNDMRFG (SEQ ID NO: 11), and the TCR beta chain comprises a CDR3 beta comprising the sequence of ASSQGRWYEAF (SEQ ID NO: 13).

43. An engineered T-cell receptor (TCR), wherein the TCR comprises an amino acid that shares at least 90% sequence identity to the sequence as set forth in SEQ ID NO:03.

44. The engineered TCR of claim 43, wherein the TCR comprises a TCR alpha chain of

SEQ ID NO: 4 and a TCR beta chain of SEQ ID NO:6.

45. The engineered TCR of claim 44, wherein the TCR alpha chain comprises a CDR3 alpha comprising the sequence AWNNNDMRFG (SEQ ID NO:5), and the TCR beta chain comprises a CDR3 beta comprising the sequence of ASSPGRWYEQF (SEQ ID NO:7).

46. An engineered T-cell receptor (TCR), wherein the TCR comprises an amino acid that shares at least 90% sequence identity to the sequence as set forth in SEQ ID NO:09.

47. The engineered TCR of claim 46, wherein the TCR comprises a TCR alpha chain of

SEQ ID NO: 10 and a TCR beta chain of SEQ ID NO: 12.

48. The engineered TCR of claim 47, wherein the TCR alpha chain comprises a CDR3 alpha comprising the sequence AVLNNNDMRFG (SEQ ID NO: 11), and the TCR beta chain comprises a CDR3 beta comprising the sequence of ASSQGRWYEAF (SEQ ID NO: 13).

49. The engineered TCR of any of claims 43-48, wherein the engineered TCR specifically binds to a LMP2 antigen.

50. The engineered TCR of claim 49, wherein the LMP2 antigen comprises

SSCSSCPLSK (SEQ ID NO: 1).

51. A pharmaceutical composition comprising a population of T-cells expressing the engineered TCR according to any of claims 43-50, and a pharmaceutically acceptable carrier.

52. A method of inducing a T-cell response in a subject suffering from a cancer comprising LMP2, wherein the method comprises administering to the subject a

therapeutically effective amount of a population of T-cells comprising the engineered TCR of any of claims 43-50, or the pharmaceutical composition of claim 51, wherein the

administration induces an anti-tumor response to the cancer.

53. The method of claim 52, wherein the cancer is selected from group consisting of nasopharyngeal carcinoma (NPC), lymphoma, gastric cancer, lung cancer, melanoma, breast cancer, prostate cancer, colon cancer, renal cell carcinoma, ovarian cancer, neuroblastoma, rhabdomyosarcoma, and leukemia.

54. The method of claim 53, wherein the cancer is an EBV -associated cancer.

55. The method of claim 52, wherein the cancer is nasopharyngeal carcinoma (NPC).

56. The method of claim 52, wherein the cancer is lymphoma.

57. The method of claim 52, wherein the cancer is gastric cancer.