Compositions and methods for treating cancer

• US 9,402,865 B2
• Filed: 01/18/2012
• Issued: 08/02/2016
• Est. Priority Date: 01/18/2011
• Status: Active Grant

• Current Assignee: Fondazione Irccs Istituto Nazionale Dei Tumori, Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: Powell, Daniel J., Coukos, George
• Primary Examiner(s): Long, Scott
• Application Number:
  US13/979,927
• Publication Number:
  US 20140050708A1
• Time in Patent Office: 1,658 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2035/124 the cells being hematopoietic, bone marrow derived or blood cells
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2239/59 Reproductive system, e.g. uterus, ovaries, cervix or testes
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 39/4611 T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
• CPC Class Codes: A61K 39/4631 Chimeric Antigen Receptors [CAR]
• CPC Class Codes: A61K 39/464402 Receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C07K 14/7051 T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 14/70517 CD8
• CPC Class Codes: C07K 14/70578 NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 NGF-receptor C07K14/71, TNF-receptor C07K14/7151
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2318/20 Antigen-binding scaffold molecules wherein the scaffold is not an immunoglobulin variable region or antibody mimetics
• CPC Class Codes: C07K 2319/02 containing a signal sequence
• CPC Class Codes: C07K 2319/03 containing a transmembrane segment
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 2319/74 containing a fusion for binding to a cell surface receptor
• CPC Class Codes: C12N 5/0636 : T lymphocytes

Abstract

The invention provides compositions and methods for treating ovarian cancer. Specifically, the invention relates to administering a genetically modified T cell having α-folate receptor (FRα) binding domain and 4-1BB (CD137) costimulatory domain to treat ovarian cancer.

Claims

1. An isolated nucleic acid sequence encoding a chimeric antigen receptor (CAR), wherein the isolated nucleic acid sequence comprises a nucleic acid sequence encoding an anti-α

-folate receptor (FRα

) antibody or fragment thereof comprising the amino acid sequence of SEQ ID NO;

23 and a 4-1BB (CD

     137) costimulatory domain.

2. The isolated nucleic acid sequence of claim 1, further comprising a nucleic acid sequence encoding a CD3 zeta signaling domain.

3. The isolated nucleic acid sequence of claim 1, wherein the CAR comprises an amino acid sequence of SEQ ID NO:

22.

4. The isolated nucleic acid sequence of claim 1 comprising a nucleic acid sequence of SEQ ID NO:

20.

5. The isolated nucleic acid sequence of claim 1, wherein the anti-FRα

antibody or fragment thereof binds to a tumor antigen, wherein the tumor antigen is FRα

.

6. The isolated nucleic acid sequence of claim 5, wherein the tumor antigen is associated with an epithelial malignancy.

7. The isolated nucleic acid sequence of claim 5, wherein the tumor antigen is associated with a solid tumor.

8. The isolated nucleic sequence of claim 1, wherein the 4-1BB costimulatory domain comprises an amino acid sequence of SEQ ID NO:

18.

9. The isolated nucleic acid sequence of claim 1, wherein the 4-1BB costimulatory domain is encoded by the nucleic acid sequence of SEQ ID NO:

6.

10. The isolated nucleic sequence of claim 2, wherein the CD3 zeta signaling domain comprises an amino acid sequence of SEQ ID NO:

19.

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

7.

12. The isolated nucleic acid sequence of claim 1, further comprising the nucleic acid sequence of a transmembrane domain.

22. A genetically modified T cell comprising the isolated nucleic acid sequence of claim 1.

23. A vector comprising the isolated nucleic acid sequence of claim 1.

24. A method for providing an anti-tumor immunity in a subject, the method comprising:

administering to the subject an effective amount of the genetically modified T cell of claim 22, thereby providing anti-tumor immunity in a subject.

25. The method of claim 24, wherein the isolated nucleic acid sequence further comprises the nucleic acid sequence of a CD3 zeta signaling domain.

26. The method of claim 24, wherein the presence of the costimulatory domain enhances T cell survival.

27. The method of claim 24, wherein the presence of the costimulatory domain increases the efficacy of anti-tumor immunity in a subject.

28. The method of claim 24, wherein the subject is a mammal.

29. The method of claim 24, wherein the subject is a human.

30. A method for stimulating a T-cell mediated immune response to a cell population or tissue in a subject, the method comprising:

administering to the subject an effective amount of the genetically modified T cell of claim 22, thereby stimulating a T-cell mediated immune response in the subject.

31. A method for treating an ovarian cancer in a subject, the method comprising:

administering to the subject an effective amount of the genetically modified T cell of claim 22, thereby treating the ovarian cancer in the subject.

32. A method for treating an cancer in a subject, the method comprising:

administering to the subject an effective amount of the genetically modified T cell of claim 22, thereby treating the cancer in the subject.

33. A method for generating a persisting population of genetically engineered T cells in a subject diagnosed with ovarian cancer, the method comprising:

administering to the subject an effective amount of the genetically modified T cell of claim 22, wherein the persisting population of genetically engineered T cells persists in the subject for at least one month after administration.

34. The method of claim 33, wherein the persisting population of genetically engineered T cells persists in the human for at least three months after administration.

13. An isolated chimeric antigen receptor (CAR), wherein the CAR comprises an anti-α

-folate receptor (FRα

) antibody or fragment thereof comprising the amino acid sequence of SEQ ID NO;

23 and a 4-1BB (CD

     137) costimulatory domain.

14. The isolated CAR of claim 13 further comprising a CD3 zeta signaling domain.

15. The isolated CAR of claim 13, wherein the CAR comprises the amino acid sequence of SEQ ID NO:

22.

16. The isolated CAR of claim 13, wherein the FRα

binding domain binds to a tumor antigen, wherein the tumor antigen is FRα

.

17. The isolated CAR of claim 16, wherein the tumor antigen is associated with an epithelial malignancy.

18. The isolated CAR of claim 16, wherein the tumor antigen is associated with a solid tumor.

19. The isolated CAR of claim 13, wherein the 4-1BB costimulatory domain comprises the amino acid sequence of SEQ ID NO:

18.

20. The isolated CAR of claim 14, wherein the CD3 zeta signaling domain comprises the amino acid sequence of SEQ ID NO:

19.

21. The isolated CAR of claim 13, further comprising a transmembrane domain.