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 chimeric antigen receptor (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.
2. The isolated CAR of claim 1 , wherein the stromal cell antigen is expressed on a stromal cell present in a tumor microenvironment.
3. The isolated CAR of claim 2 , wherein the tumor is a carcinoma.
4. The isolated CAR of claim 1 , wherein the stromal cell antigen is fibroblast activation protein (FAP).
5. The isolated CAR 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 CAR of claim 1 , wherein the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO: 1.
7. The isolated CAR of claim 1 , wherein the transmembrane domain is encoded by a nucleic acid sequence comprising SEQ ID NO: 5.
8. The isolated CAR of claim 1 , wherein the costimulatory signaling region is encoded by a nucleic acid sequence comprising SEQ ID NO: 6.
9. The isolated CAR of claim 1 , wherein the CD3 zeta signaling domain is encoded by a nucleic acid sequence comprising SEQ ID NO: 7.