USE OF ICOS-BASED CARS TO ENHANCE ANTITUMOR ACTIVITY AND CAR PERSISTENCE

• US 20150017141A1
• Filed: 02/22/2013
• Published: 01/15/2015
• Est. Priority Date: 02/22/2012
• Status: Active Grant

• Current Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: June, Carl H., Zhao, Yangbing, Scholler, John, Guedan Carrio, Sonia
• Granted Patent: US 9,714,278 B2
• Time in Patent Office: Days
• US Class Current: 424/93.21
• CPC Class Codes: A61K 35/12 Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells vaccines or medicinal preparations containing antigens or antibodies A61K39/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C07K 14/70503 Immunoglobulin superfamily
• CPC Class Codes: C07K 14/7051 T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 14/70517 CD8
• CPC Class Codes: C07K 14/70521 CD28, CD152
• CPC Class Codes: C07K 2319/03 containing a transmembrane segment
• CPC Class Codes: C12N 5/10 Cells modified by introduction of foreign genetic material

Abstract

The present invention provides compositions and methods for treating cancer in a human. The invention includes administering a genetically modified Th17 cell to express a CAR having an antigen binding domain, a transmembrane domain, and an ICOS intracellular signaling domain.

Claims

1. An isolated nucleic acid sequence encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain, a transmembrane domain, and an ICOS intracellular signaling domain.

2. The isolated nucleic acid sequence of claim 1, further comprising a CD3zeta signaling domain.

3. The isolated nucleic acid sequence of claim 1, comprising the nucleic acid sequence of SEQ ID NO:

8.

4. The isolated nucleic acid sequence of claim 1, wherein the antigen binding domain is an antibody or an antigen-binding fragment thereof.

5. The isolated nucleic acid sequence of claim 4, wherein the antigen-binding fragment is a Fab or a scFv.

6. The isolated nucleic acid sequence of claim 1, wherein the antigen binding domain binds to a tumor antigen.

7. The isolated nucleic acid sequence of claim 1, further comprising a costimulatory signaling region comprising the intracellular domain of a costimulatory molecule selected from the group consisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, and any combination thereof.

8. The isolated nucleic acid sequence of claim 1, wherein the ICOS intracellular signaling domain is encoded by the nucleic acid sequence of SEQ ID NO:

6.

9. The isolated nucleic acid sequence of claim 2, wherein the CD3 zeta signaling domain is encoded by the nucleic acid sequence of SEQ ID NO:

7.

10. A cell comprising a nucleic acid sequence encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain, a transmembrane domain, and an ICOS intracellular signaling domain.

11. The cell of claim 10, wherein the CAR further comprises a CD3zeta signaling domain.

12. The cell of claim 10, wherein the nucleic acid sequence comprises the nucleic acid sequence of SEQ ID NO:

8.

13. The cell of claim 10, wherein the antigen binding domain is an antibody or an antigen-binding fragment thereof.

14. The cell of claim 13, wherein the antigen-binding fragment is a Fab or a scFv.

15. The cell of claim 10, wherein the antigen binding domain binds to a tumor antigen.

16. The cell of claim 10, wherein the CAR further comprises a costimulatory signaling region comprising the intracellular domain of a costimulatory molecule selected from the group consisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, and any combination thereof.

17. The cell of claim 10, wherein the ICOS intracellular signaling domain is encoded by the nucleic acid sequence of SEQ ID NO:

6.

18. The cell of claim 11, wherein the CD3 zeta signaling domain is encoded by the nucleic acid sequence of SEQ ID NO:

7.

19. The cell of claim 10, wherein the cell is selected from the group consisting of a Th17 cell and a Tc17 cell.

20. The cell of claim 10, wherein the cell exhibits an anti-tumor immunity when the antigen binding domain binds to its corresponding antigen.

21. A method for stimulating a T cell-mediated immune response to a target cell population or tissue in a mammal, the method comprising administering to a mammal an effective amount of a cell genetically modified to express a CAR, wherein the CAR comprises an antigen binding domain, a transmembrane domain, and an ICOS intracellular signaling domain.

22. The method of claim 21, wherein the CAR further comprises a CD3zeta signaling domain.

23. A method of providing an anti-tumor immunity in a mammal, the method comprising administering to the mammal an effective amount of a cell genetically modified to express a CAR, wherein the CAR comprises an antigen binding domain, a transmembrane domain, and an ICOS intracellular signaling domain, thereby providing an anti-tumor immunity in the mammal.

24. The method of claim 23, wherein the CAR further comprises a CD3zeta signaling domain.

25. 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 mammal an effective amount of a cell genetically modified to express a CAR, wherein the CAR comprises an antigen binding domain, a transmembrane domain, and an ICOS intracellular signaling domain, thereby treating the mammal.

26. The method of claim 25, wherein the CAR further comprises a CD3zeta signaling domain.

27. The method of claim 25, wherein the cell is selected from the group consisting of an autologous Th17 cell and an autologous Tc17 cell.

28. A method of treating a human with cancer, the method comprising administering to the human a cell genetically engineered to express a CAR, wherein the CAR comprises an antigen binding domain, a transmembrane domain, and an ICOS intracellular signaling domain, wherein the cell is selected from the group consisting of a Th17 cell and a Tc17 cell.

29. The method of claim 28, wherein the CAR further comprises a CD3zeta signaling domain.

30. The method of claim 28, wherein the human is resistant to at least one chemotherapeutic agent.

31. A method of generating a persisting population of genetically engineered T cells in a human diagnosed with cancer, the method comprising administering to the human a cell genetically engineered to express a CAR, wherein the CAR comprises an antigen binding domain, a transmembrane domain, and an ICOS intracellular signaling domain, wherein the persisting population of genetically engineered cells persists in the human for at least one month after administration, and wherein the cell is selected from the group consisting of a Th17 cell and a Tc17 cell.

32. The method of claim 31, wherein the CAR further comprises a CD3zeta signaling domain.

33. The method of claim 31, wherein the persisting population of genetically engineered T cells comprises at least one cell selected from the group consisting of a cell that was administered to the human, a progeny of a cell that was administered to the human, and a combination thereof.

34. The method of claim 31, wherein the persisting population of genetically engineered T cells comprises a memory T cell.

35. The method of claim 31, wherein the persisting population of genetically T engineered cells persists in the human for at least three months after administration.

36. The method of claim 31, wherein the persisting population of genetically engineered T cells persists in the human for at least four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, two years, or three years after administration.

37. The method of claim 31, wherein the cancer is treated.

38. A method of expanding a population of genetically engineered T cells in a human diagnosed with cancer, the method comprising administering to the human a cell genetically engineered to express a CAR, wherein the CAR comprises an antigen binding domain, a transmembrane domain, and an ICOS intracellular signaling domain, wherein the administered genetically engineered cell is selected from the group consisting of a Th17 cell and a Tc17 cell, further wherein the administered genetically engineered cell produces a population of progeny T cells in the human.

39. The method of claim 38, wherein the CAR further comprises a CD3zeta signaling domain.

40. The method of claim 38, wherein the progeny T cells in the human comprise a memory T cell.

41. The method of claim 38, wherein the cell is an autologous cell.

42. The method of claim 38, wherein the population of progeny T cells persists in the human for at least three months after administration.

43. The method of claim 38, wherein the population of progeny T cells persist in the human for at least four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, two years, or three years after administration.

44. The method of claim 38, wherein the cancer is treated.