Compositions and methods for targeting stromal cells for the treatment of cancer
The present invention provides compositions and methods for treating cancer in a human. The invention relates to targeting the stromal cell population in a tumor microenvironment. For example, in one embodiment, the invention provides a composition that is targeted to fibroblast activation protein (FAP). The invention includes a chimeric antigen receptor (CAR) which comprises an anti-FAP domain, a transmembrane domain, and a CD3zeta signaling domain.
1. An isolated nucleic acid sequence encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain encoded by a nucleic acid sequence comprising SEQ ID NO: 3, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain, wherein the antigen binding domain binds to a stromal cell antigen.
2. The isolated nucleic acid sequence of claim 1 , wherein the stromal cell antigen is expressed on a stromal cell present in a tumor microenvironment.
3. The isolated nucleic acid sequence of claim 2 , wherein the tumor is a carcinoma.
4. The isolated nucleic acid of claim 1 , wherein the stromal cell antigen is fibroblast activation protein (FAP).
5. The isolated nucleic acid sequence of claim 1 , wherein the costimulatory signaling region comprises the intracellular domain of a costimulatory molecule selected from the group consisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, and any combination thereof.
6. The isolated nucleic acid sequence of claim 1 , wherein the nucleic acid sequence comprises SEQ ID NO: 1.
7. A cell comprising a nucleic acid sequence encoding a chimeric antigen receptor (CAR), the CAR comprising an antigen binding domain encoded by a nucleic acid sequence comprising SEQ ID NO: 3, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain, wherein the antigen binding domain binds to a stromal cell antigen.
8. The cell of claim 7 , wherein the stromal cell antigen is expressed on a stromal cell present in a tumor microenvironment.
9. The cell of claim 8 , wherein the tumor is a carcinoma.
10. The cell of claim 7 , wherein the stromal cell antigen is FAP.
11. The cell of claim 7 , wherein the costimulatory signaling region comprises the intracellular domain of a costimulatory molecule selected from the group consisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, and any combination thereof.
12. The cell of claim 7 , wherein the cell is selected from the group consisting of a T cell, a natural killer (NK) cell, a cytotoxic T lymphocyte (CTL), and a regulatory T cell.
13. The cell of claim 7 , wherein the nucleic acid sequence comprises SEQ ID NO: 1.
14. A vector comprising a nucleic acid sequence encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain encoded by a nucleic acid sequence comprising SEQ ID NO: 3, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain, wherein the antigen binding domain binds to a stromal cell antigen.
15. The vector of claim 14 , wherein the stromal cell antigen is expressed on a stromal cell present in a tumor microenvironment.
16. The vector of claim 15 , wherein the tumor is a carcinoma.
17. The vector of claim 14 , wherein the stromal cell antigen is FAP.
18. The vector of claim 14 , wherein the costimulatory signaling region comprises the intracellular domain of a costimulatory molecule selected from the group consisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, and any combination thereof.
19. The vector of claim 14 , wherein the nucleic acid sequence comprises SEQ ID NO: 1.
20. A composition comprising a cell comprising a nucleic acid sequence encoding a chimeric antigen receptor (CAR), the CAR comprising an antigen binding domain encoded by a nucleic acid sequence comprising SEQ ID NO: 3, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain, wherein the antigen binding domain binds to a stromal cell antigen, in combination with an antitumor vaccine.
21. The isolated nucleic acid of claim 1 , wherein the transmembrane domain is encoded by a nucleic acid sequence comprising SEQ ID NO: 5.
22. The cell of claim 7 , wherein the transmembrane domain is encoded by a nucleic acid sequence comprising SEQ ID NO: 5.
23. The vector of claim 14 , wherein the transmembrane domain is encoded by a nucleic acid sequence comprising SEQ ID NO: 5.
24. The isolated nucleic acid of claim 1 , wherein the costimulatory signaling region is encoded by a nucleic acid sequence comprising SEQ ID NO: 6.
25. The cell of claim 7 , wherein the costimulatory signaling region is encoded by a nucleic acid sequence comprising SEQ ID NO: 6.
26. The vector of claim 14 , wherein the costimulatory signaling region is encoded by a nucleic acid sequence comprising SEQ ID NO: 6.