Compositions and methods for targeting stromal cells for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-9365641-B2
Application number	US-201314042306-A
Country	US
Kind code	B2
Filing date	Sep 30, 2013
Priority date	Oct 1, 2012
Publication date	Jun 14, 2016
Grant date	Jun 14, 2016

Abstract

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.

First claim

What is claimed is:

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.

Assignees

• Univ Pennsylvania
• Wistar Inst

Inventors

• June Carl H
• Pure Ellen
• Wang Liang-Chuan
• Albelda Steven
• Scholler John

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07K16/40 Primary

  against enzymes · CPC title

• C07K14/70578

  NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 (NGF-receptor C07K14/71, TNF-receptor C07K14/7151) · CPC title

• C07K2319/03

  containing a transmembrane segment · CPC title

• C07K14/70517

  CD8 · CPC title