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1. (WO2018129524) COMPOSITIONS AND METHODS FOR TREATING CANCER WITH ANTI-MESOTHELIN IMMUNOTHERAPY
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WHAT IS CLAIMED IS:

1. An isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR) comprising at least one extracellular antigen binding domain comprising a mesothelin antigen binding domain encoded by a nucleotide sequence comprising SEQ ID NO. 1, 3, 5, or 7, at least one transmembrane domain, and at least one intracellular signaling domain.

2. The isolated nucleic acid molecule of claim 1 , wherein the encoded at least one mesothelin antigen binding domain comprises at least one single chain variable fragment of an antibody that binds to mesothelin.

3. The isolated nucleic acid molecule of claim 1 , wherein the encoded at least one mesothelin antigen binding domain comprises at least one heavy chain variable region of an antibody that binds to mesothelin.

4. The isolated nucleic acid molecule of claim 1 , wherein the encoded at least one mesothelin antigen binding domain, the at least one intracellular signaling domain, or both are connected to the transmembrane domain by a linker or spacer domain.

5. The isolated nucleic acid molecule of claim 4, wherein the encoded linker or spacer domain is derived from the extracellular domain of CD8 or CD28, and is linked to a transmembrane domain.

6. The isolated nucleic acid molecule of claim 1, wherein the encoded extracellular mesothelin antigen binding domain is preceded by a leader nucleotide sequence encoding a leader peptide.

7. The isolated nucleic acid molecule of claim 6, wherein the leader nucleotide sequence comprises a nucleotide sequence comprising SEQ ID NO: 9 encoding the leader amino acid sequence of SEQ ID NO: 10.

8. The isolated nucleic acid molecule of claim 1, wherein the transmembrane domain comprises a transmembrane domain of a protein comprising the alpha, beta or zeta chain of the T-cell receptor, CD8, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154, or any combination thereof.

9. The isolated nucleic acid molecule of claim 1, wherein the nucleic acid sequence encoding the extracellular mesothelin antigen binding domain comprises a nucleic sequence comprising SEQ ID NO: 1, 3, 5, or 7, or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof.

10. The isolated nucleic acid molecule of claim 1, wherein the encoded at least one intracellular signaling domain further comprises a CD3 zeta intracellular domain.

11. The isolated nucleic acid molecule of claim 10, wherein the encoded at least one intracellular signaling domain is arranged on a C-terminal side relative to the CD3 zeta intracellular domain.

12. The isolated nucleic acid molecule of claim 1, wherein the encoded at least one intracellular signaling domain comprises a costimulatory domain, a primary signaling domain, or any combination thereof.

13. The isolated nucleic acid molecule of claim 12, wherein the encoded at least one costimulatory domain comprises a functional signaling domain of OX40, CD70, CD27, CD28, CD5, ICAM-1, LFA-1 (CD1 la/CD18), ICOS (CD278), DAP10, DAP 12, and 4-1BB (CD137), or any combination thereof.

14. A chimeric antigen receptor (CAR) encoded by the isolated nucleic acid molecule of claim 1.

15. The CAR of claim 14, comprising at least one extracellular antigen binding domain comprising a mesothelin antigen binding domain comprising the amino acid sequence of SEQ ID NO. 2, 4, 6, or 8, at least one transmembrane domain, and at least one intracellular signaling domain.

16. The CAR of claim 15, wherein the mesothelin antigen binding domain comprises at least one single chain variable fragment of an antibody that binds to mesothelin.

17. The CAR of claim 15, wherein the mesothelin antigen binding domain comprises at least one heavy chain variable region of an antibody that binds to mesothelin.

18. The CAR of claim 15, wherein the transmembrane domain comprises a transmembrane domain of a protein comprising the alpha, beta or zeta chain of the T- cell receptor, CD8, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154, or any combination thereof.

19. The CAR of claim 18, wherein the CD8 transmembrane domain comprises the amino acid sequence of SEQ ID NO: 19, or an amino acid sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to an amino acid sequence of SEQ ID NO: 19.

20. The CAR of claim 15, wherein the at least one extracellular antigen binding domain comprising a mesothelin antigen binding domain comprising the amino acid sequence of SEQ ID NO. 2, 4, 6, or 8, and the at least one intracellular signaling domain, or both are connected to the transmembrane domain by a linker or spacer domain.

21. The CAR of claim 20, wherein the linker or spacer domain is derived from the extracellular domain of CD8 or CD28, and is linked to a transmembrane domain.

22. The CAR of claim 17, wherein the at least one intracellular signaling domain comprises a costimulatory domain and a primary signaling domain.

23. The CAR of claim 22, wherein the at least one intracellular signaling domain comprises a costimulatory domain comprising a functional signaling domain of a protein selected from the group consisting of OX40, CD70, CD27, CD28, CD5, ICAM-1, LFA-1 (CD1 la/CD18), ICOS (CD278), DAP10, DAP 12, and 4-1BB (CD 137), or a combination thereof.

24. A vector comprising a nucleic acid molecule of claim 1.

25. The vector of claim 24, wherein the vector is selected from the group consisting of a DNA vector, an RNA vector, a plasmid vector, a cosmid vector, a herpes virus vector, a measles virus vector, a lentivirus vector, adenoviral vector, or a retrovirus vector, or a combination thereof.

26. The vector of claim 24, further comprising a promoter.

27. The vector of claim 26, wherein the promoter is an inducible promoter, a constitutive promoter, a tissue specific promoter, a suicide promoter or any combination thereof.

28. A cell comprising the vector of claim 24.

29. The cell of claim 28, wherein the cell is a T cell.

30. The cell of claim 28, wherein the T cell is a CD8+ T cell.

31. The cell of claim 28, wherein the cell is a human cell.

32. A method of making a cell comprising transducing a T cell with a vector of claim 24.

33. A method of generating a population of RNA-engineered cells comprising introducing an in vitro transcribed RNA or synthetic RNA into a cell, where the RNA comprises a nucleic acid molecule of claim 1.

34. A method of providing an anti-tumor immunity in a mammal comprising administering to the mammal an effective amount of a cell of claim 28.

35. A method of treating or preventing cancer in a mammal, comprising administering to the mammal the CAR of claim 15, in an amount effective to treat or prevent cancer in the mammal.

36. A pharmaceutical composition comprising an anti-tumor effective amount of a population of human T cells, wherein the T cells comprise a nucleic acid sequence that encodes a chimeric antigen receptor (CAR), wherein the CAR comprises at least one extracellular antigen binding domain comprising a mesothelin antigen binding domain comprising the amino acid sequence of SEQ ID NO. 2, 4, 6, 8, at least one linker domain, at least one transmembrane domain, at least one intracellular signaling domain, and wherein the T cells are T cells of a human having a cancer.

37. The pharmaceutical composition of claim 36, wherein the at least one transmembrane domain comprises a transmembrane domain of a protein comprising the alpha, beta or zeta chain of the T-cell receptor, CD8, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154, or any combination thereof.

38. The pharmaceutical composition of claim 36, wherein the T cells are T cells of a human having a hematological cancer.

39. The pharmaceutical composition of claim 38, wherein the hematological cancer is leukemia or lymphoma.

40. The pharmaceutical composition of claim 39, wherein the leukemia is chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), or chronic myelogenous leukemia (CML).

41. The pharmaceutical composition of claim 39, wherein the lymphoma is mantle cell lymphoma, non-Hodgkin's lymphoma or Hodgkin's lymphoma.

42. The pharmaceutical composition of claim 38, wherein the hematological cancer is multiple myeloma.

43. The pharmaceutical composition of claim 36, wherein the human cancer includes an adult carcinoma comprising oral and pharynx cancer (tongue, mouth, pharynx, head and neck), digestive system cancers (esophagus, stomach, small intestine, colon, rectum, anus, liver, interhepatic bile duct, gallbladder, pancreas), respiratory system cancers (larynx, lung and bronchus), bones and joint cancers, soft tissue cancers, skin cancers (melanoma, basal and squamous cell carcinoma), pediatric tumors (neuroblastoma, rhabdomyosarcoma, osteosarcoma, Ewing's sarcoma), tumors of the central nervous system (brain, astrocytoma, glioblastoma, glioma), and cancers of the breast, the genital system (uterine cervix, uterine corpus, ovary, vulva, vagina, prostate, testis, penis, endometrium), the urinary system (urinary bladder, kidney and renal pelvis, ureter), the eye and orbit, the endocrine system (thyroid), and the brain and other nervous system, or any combination thereof.

44. A method of treating a mammal having a disease, disorder or condition associated with an elevated expression of a tumor antigen, the method comprising administering to the subject a pharmaceutical composition comprising an anti -tumor effective amount of a population of T cells, wherein the T cells comprise a nucleic acid sequence that encodes a chimeric antigen receptor (CAR), wherein the CAR comprises at least one extracellular antigen binding domain comprising a mesothelin antigen binding domain comprising the amino acid sequence of SEQ ID NO. 2, 4, 6, or 8, at least one linker or spacer domain, at least one transmembrane domain, at least one intracellular signaling domain, wherein the T cells are T cells of the subject having cancer.

45. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an anti -tumor effective amount of a population of T cells, wherein the T cells comprise a nucleic acid sequence that encodes a chimeric antigen receptor (CAR), wherein the CAR comprises at least one extracellular antigen binding domain comprising a mesothelin antigen binding domain comprising the amino acid sequence of SEQ ID NO. 2, 4, 6, or 8, at least one linker or spacer domain, at least one transmembrane domain, at least one intracellular signaling domain, wherein the T cells are T cells of the subject having cancer.

46. The method of claim 44 or 45, wherein the at least one transmembrane domain comprises a transmembrane domain of a protein comprising the alpha, beta or zeta chain of the T-cell receptor, CD8, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9,

CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154, or any combination thereof.

47. A process for producing a chimeric antigen receptor-expressing cell, the process comprising introducing the isolated nucleic acid of claim 1 into a cell.

48. The process for producing a chimeric antigen receptor-expressing cell according to claim 47, wherein the cell is a T cell or a cell population containing a T cell.