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 α-folate receptor (FRα) antibody comprising the amino acid sequence of SEQ ID NO: 15.
2 . The isolated nucleic acid sequence of claim 1 , wherein the CAR further comprises a CD3 zeta signaling domain.
3 . The isolated nucleic acid sequence of claim 2 , wherein the CD3 zeta signaling domain comprises an amino acid sequence of SEQ ID NO: 19.
4 . 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.
5 . The isolated nucleic acid sequence of claim 1 , wherein the CAR further comprises a transmembrane domain.
6 . An isolated chimeric antigen receptor (CAR), wherein the CAR comprises an α-folate receptor (FRα) antibody comprising the amino acid sequence of SEQ ID NO: 15.
7 . The isolated CAR of claim 6 , wherein the CAR further comprises a CD3 zeta signaling domain.
8 . The isolated CAR of claim 7 , wherein the CD3 zeta signaling domain comprises an amino acid sequence of SEQ ID NO: 19.
9 . The isolated CAR of claim 7 , wherein the CD3 zeta signaling domain is encoded by a nucleic acid sequence of SEQ ID NO: 7.
10 . The isolated CAR of claim 6 , wherein the CAR further comprises a transmembrane domain.
11 . A method for providing anti-tumor immunity in a subject, the method comprising: administering to the subject an effective amount of a T cell comprising the CAR of claim 6 , thereby providing anti-tumor immunity in the subject.
12 . The method of claim 11 , wherein the CAR further comprises a 4-1BB costimulatory domain
13 . The method of claim 12 , wherein the 4-1BB costimulatory domain comprises an amino acid sequence of SEQ ID NO: 18.
14 . The method of claim 12 , wherein the 4-1BB costimulatory domain is encoded by the nucleic acid sequence of SEQ ID NO: 6.
15 . 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 a T cell comprising the CAR of claim 6 , thereby stimulating a T cell-mediated immune response in the subject.
16 . The method of claim 15 , wherein the CAR further comprises a 4-1BB costimulatory domain.
17 . The method of claim 16 , wherein the 4-1BB costimulatory domain comprises an amino acid sequence of SEQ ID NO: 18.
18 . The method of claim 16 , wherein the 4-1BB costimulatory domain is encoded by the nucleic acid sequence of SEQ ID NO: 6.
19 . A method for treating an ovarian cancer in a subject, the method comprising:
administering to the subject an effective amount of a T cell comprising the CAR of claim 6 , thereby treating the ovarian cancer in the subject.
20 . The method of claim 19 , wherein the CAR further comprises a 4-1BB costimulatory domain
21 . The method of claim 20 , wherein the 4-1BB costimulatory domain comprises an amino acid sequence of SEQ ID NO: 18.
22 . The method of claim 20 , wherein the 4-1BB costimulatory domain is encoded by the nucleic acid sequence of SEQ ID NO: 6.
23 . A method for treating cancer in a subject, the method comprising:
administering to the subject an effective amount of a T cell comprising the CAR of claim 6 , thereby treating cancer in the subject.
24 . The method of claim 23 , wherein the CAR further comprises a 4-1BB costimulatory domain
25 . The method of claim 24 , wherein the 4-1BB costimulatory domain comprises an amino acid sequence of SEQ ID NO: 18.
26 . The method of claim 24 , wherein the 4-1BB costimulatory domain is encoded by the nucleic acid sequence of SEQ ID NO: 6.
27 . A method of 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 a T cell comprising the CAR of claim 6 , wherein the persisting population of genetically engineered T cells persists in the subject for at least one month after administration.
28 . The method of claim 27 , wherein the CAR further comprises a 4-1BB costimulatory domain
29 . The method of claim 28 , wherein the 4-1BB costimulatory domain comprises an amino acid sequence of SEQ ID NO: 18.
30 . The method of claim 28 , wherein the 4-1BB costimulatory domain is encoded by the nucleic acid sequence of SEQ ID NO: 6.
31 . The isolated nucleic acid sequence of claim 1 , wherein the CAR comprises the amino acid sequence of SEQ ID NO: 13.
32 . The isolated nucleic acid sequence of claim 1 , wherein the CAR is encoded by the nucleic acid sequence of SEQ ID NO: 1.
33 . The isolated CAR of claim 6 , wherein the CAR comprises the amino acid sequence of SEQ ID NO: 13.
34 . The isolated CAR of claim 6 , wherein the CAR is encoded by the nucleic acid sequence of SEQ ID NO: 1.
35 . The method of claim 11 , wherein the CAR comprises the amino acid sequence of SEQ ID NO: 13.
36 . The method of claim 11 , wherein the CAR is encoded by the nucleic acid sequence of SEQ ID NO: 1.
37 . The method of claim 15 , wherein the CAR comprises the amino acid sequence of SEQ ID NO: 13.
38 . The method of claim 15 , wherein the CAR is encoded by the nucleic acid sequence of SEQ ID NO: 1.
39 . The method of claim 19 , wherein the CAR comprises the amino acid sequence of SEQ ID NO: 13.
40 . The method of claim 19 , wherein the CAR is encoded by the nucleic acid sequence of SEQ ID NO: 1.
41 . The method of claim 23 , wherein the CAR comprises the amino acid sequence of SEQ ID NO: 13.
42 . The method of claim 23 , wherein the CAR is encoded by the nucleic acid sequence of SEQ ID NO: 1.
43 . The method of claim 27 , wherein the CAR comprises the amino acid sequence of SEQ ID NO: 13.
44 . The method of claim 27 , wherein the CAR is encoded by the nucleic acid sequence of SEQ ID NO: 1.