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Machine translation
1. (WO2014158811) NEWCASTLE DISEASE VIRUSES AND USES THEREOF
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

WHAT IS CLAIMED:

1. A chimeric Newcastle disease virus (NDV), comprising a packaged genome which encodes an agonist of a co-stimulatory receptor of an immune cell, wherein the agonist is expressed by the virus.

2. A chimeric NDV, comprising a packaged genome which encodes an antagonist of an inhibitory receptor of an immune cell, wherein the antagonist is expressed by the virus.

3. The chimeric NDV of claim 1 or 2, wherein the packaged genome encodes a mutated F protein and the mutated F protein is expressed by the virus.

4. The chimeric NDV of claim 1 or 2, wherein the immune cell is a T lymphocyte or natural killer (NK) cell.

5. The chimeric NDV of claim 1, wherein the co-stimulatory receptor is

glucocorticoid-induced tumor necrosis factor receptor (GITR), OX40, CD27, CD28, 4-lBB or CD40.

6. The chimeric NDV of claim 2, wherein the inhibitory receptor is cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PDl), B and T-lymphocyte attenuator (BTLA), killer cell immunoglobulin-like receptor (KIR), lymphocyte activation gene 3 (LAG3), or T-cell membrane protein 3 (TIM3).

7. The chimeric NDV of claim 1, wherein the agonist is an antibody that specifically binds to the co-stimulatory receptor.

8. The chimeric NDV of claim 1, wherein the agonist is a ligand that specifically binds to the co-stimulatory receptor.

9. The chimeric NDV of claim 1, wherein the agonist is an antibody specifically binds to GITR, OX40, CD27, CD28, 4-lBB or CD40.

10. The chimeric NDV of claim 7 or 9, wherein the antibody is a monoclonal antibody or single-chain Fv.

11. The chimeric NDV of claim 8, wherein the ligand is GITRL, CD40L, CD 137L, OX40L, CD70, or ICOSL.

12. The chimeric NDV of claim 2, wherein the antagonist is an antibody that specifically binds to the inhibitory receptor.

13. The chimeric NDV of claim 2, wherein the antagonist is an antibody that specifically binds to CTLA-4, PD-1, BTLA, KIR, LAG3, or TIM3.

14. The chimeric NDV of claim 2, wherein the antagonist is a soluble receptor of a ligand of the inhibitory receptor.

15. The chimeric NDV of claim 2, wherein the antagonist is an antibody that specifically binds to a ligand of the inhibitory receptor.

16. The chimeric NDV of claim 2, wherein the antagonist is an antibody that specifically binds to PDL1, PDL2, B7-H3, B7-H4, HVEM, or Gal9.

17. The chimeric NDV of claim 14, wherein the soluble receptor is the extracellular domain of PD1, BTLA, KIR, LAG3 or TIM3.

18. The chimeric NDV of claim 12, 13, 15 or 16, wherein the antibody is a monoclonal antibody or sc-Fv.

19. A pharmaceutical composition comprising the chimeric NDV of claim 1, 5, 7, 8, 9 or 11 and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition comprising the chimeric NDV of claim 2, 6, 12, 13, 14, 15, 16 or 17 and a pharmaceutically acceptable carrier.

21. A method for producing a pharmaceutical composition, the method comprising: a. propagating the chimeric NDV of any one of claims 1, 2, 5 to 9 or 11 to 17 in a cell line that is susceptible to a NDV infection; and

b. collecting the progeny virus,

wherein the virus is grown to sufficient quantities and under sufficient conditions that the virus is free from contamination, such that the progeny virus is suitable for formulation into a

pharmaceutical composition.

22. A method for producing a pharmaceutical composition, the method comprising: a. propagating the chimeric NDV of any one of claims 1, 2, 5 to 9 or 11 to 17 in an embryonated egg; and

b. collecting the progeny virus,

wherein the virus is grown to sufficient quantities and under sufficient conditions that the virus is free from contamination, such that the progeny virus is suitable for formulation into a

pharmaceutical composition.

23. A cell line comprising the chimeric NDV of any one of claims 1, 2, 5 to 9 or 11 to

17.

24. An embryonated egg comprising the chimeric NDV of any one of claims 1, 2, 5 to 9 or 11 to 17.

25. A method for treating cancer, comprising administering to a subject in need thereof a pharmaceutical composition comprising the chimeric NDV of any one of claims 1, 5, 7, 8, 9, or 11.

26. A method for treating cancer, comprising administering to a subject in need thereof a pharmaceutical composition comprising the chimeric NDV of any one of claims 2, 6, 12, 13, 14, 15, 16 or 17.

27. The method of claim 25, wherein the packaged genome of the chimeric NDV encodes a mutated F protein with a mutated cleavage site, so that the mutated F protein is expressed by the virus.

28. The method of claim 26, wherein the packaged genome of the chimeric NDV encodes a mutated F protein with a mutated cleavage site, so that the mutated F protein is expressed by the virus.

29. The method of claim 25 further comprising administering to the subject a second agonist of a co-stimulatory receptor of an immune cell.

30. The method of claim 26, further comprising administering to the subject an agonist of a co-stimulatory receptor of an immune cell.

31. The method of claim 26 further comprising administering to the subject a second antagonist of an inhibitory receptor of an immune cell.

32. The method of claim 25 further comprising administering to the subject an antagonist of an inhibitory receptor of an immune cell.

33. A method for treating cancer, comprising administering to a subject in need thereof an NDV and an agonist of a co-stimulatory receptor of an immune cell.

34. A method for treating cancer, comprising administering to a subject in need thereof an NDV and an antagonist of an inhibitory receptor of an immune cell.

35. The method of claim 33, wherein the NDV is a chimeric NDV and wherein the chimeric NDV comprises a packaged genome encoding a cytokine which is expressed by the virus.

36. The method of claim 34, wherein the NDV is a chimeric NDV, which comprises a packaged genome encoding a cytokine, wherein the cytokine is expressed by the virus.

37. The method of claim 33, wherein the NDV is a chimeric NDV, which comprises a packaged genome encoding a second agonist of a co-stimulatory receptor of an immune cell or an antagonist of an inhibitory receptor of an immune cell, wherein the second agonist or antagonist is expressed by the virus.

38. The method of claim 34, wherein the NDV is a chimeric NDV, which comprises a packaged genome encoding an agonist of a co-stimulatory receptor of an immune cell or a second antagonist of an inhibitory receptor of an immune cell, wherein the agonist or second antagonist is expressed by the virus.

39. The method of claim 35 or 36, wherein the cytokine is IL-2, IL-7, IL-15 or IL-21.

40. The method of claim 33, wherein the co-stimulatory receptor is GITR, OX40, CD27, CD28, 4- IBB or CD40.

41. The method of claim 34, wherein the inhibitory receptor is CTLA-4, PD 1 , BTLA, KIR, LAG3, or TIM3.

42. The method of claim 33, wherein the agonist is an antibody that specifically binds to the co-stimulatory receptor.

43. The method of claim 33, wherein the agonist is a ligand that specifically binds to the co-stimulatory receptor.

44. The method of claim 33, wherein the agonist is an antibody specifically binds to GITR, OX40, CD27, CD28, 4-1BB or CD40.

45. The method of claim 42 or 44, wherein the antibody is a monoclonal antibody or single-chain Fv.

46. The method of claim 43, wherein the ligand is CD137L, OX40L, CD40L, GITRL, CD70, or ICOSL.

-I l l-

47. The method of claim 34, wherein the antagonist is an antibody that specifically binds to the inhibitory receptor.

48. The method of claim 34, wherein the antagonist is an antibody that specifically binds to CTLA-4, PD1, BTLA, KIR, LAG3, or TIM3.

49. The method of claim 34, wherein the antagonist is a soluble receptor of a ligand of the inhibitory receptor.

50. The method of claim 34, wherein the antagonist is an antibody that specifically binds to a ligand of the inhibitory receptor.

51. The method of claim 34, wherein the antagonist is an antibody that specifically binds to PDL1, PDL2, B7-H3, B7-H4, HVEM, or Gal9.

52. The method of claim 51 , wherein the soluble receptor is the extracellular domain of PD1, BTLA, KIR, LAG3 or TIM3.

53. The method of claim 47, 48, 50 or 51 , wherein the antibody is a monoclonal antibody or scFv.

54. The method of claim 33 or 34 further comprising administering adoptive T lymphocytes.

55. The method of any one of claims 33 to 38, 40 to 44 or 46 to 52, wherein the cancer is melanoma, colorectal cancer, breast cancer, ovarian cancer or renal cell cancer.

56. The method of any one of claims 33 to 38, 40 to 44 or 46 to 52, wherein the cancer is malignant melanoma, malignant glioma, renal cell carcinoma, pancreatic

adenocarcinoma, malignant mesothelioma, lung adenocarcinoma, lung small cell carcinoma, lung squamous cell carcinoma, anaplastic thyroid cancer or head and neck squamous cell carcinoma.

57. The method of any one of claims 33 to 38, 40 to 44 or 46 to 52, wherein the subject is a human.