Compositions and methods for treating cancer
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.
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.
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.
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.