Compositions and Methods for Targeting Stromal Cells for the Treatment of Cancer

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.

1 .- 8 . (canceled) 
     
     
         9 . A nucleic acid encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain derived from an F19 binding domain, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain, wherein the antigen binding domain binds to a stromal cell antigen, and wherein the antigen binding domain comprises:
 (a) a light chain variable region comprising a light chain complementary region 1 comprising the amino acids 24-39 of SEQ ID NO:9 (RSSQSIVHSNGNTYLE), a light chain complementary region 2 comprising the amino acids 55-61 of SEQ ID NO: 9 (KVSNRFS), a light chain complementary region 3 comprising amino acids 94-102 of SEQ ID NO: 9 (FGGSHVPYT); or   (b) a heavy chain variable region comprising a heavy chain complementary region 1 comprising the amino acids 30-34 of SEQ ID NO: 8 (SYGMS), a heavy chain complementary region 2 comprising the amino acids 49-65 of SEQ ID NO: 8 (TTNNNGGVTYYPDSVKG), a heavy chain complementary region 3 comprising the amino acids 98-105 SEQ ID NO: 8 (YGYYAMDY).   
     
     
         10 . A vector comprising the nucleic acid of  claim 9 . 
     
     
         11 . The vector of  claim 10 , wherein the vector is a viral vector selected from the group consisting of an adenoviral vector, an adeno-associated viral vector, a retroviral vector, and a lentiviral vector. 
     
     
         12 . A modified immune cell comprising a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain derived from an F19 monoclonal antibody, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain, wherein the antigen binding domain binds to a stromal cell antigen, wherein the antigen binding domain binds to a stromal cell antigen, and wherein the antigen binding domain comprises:
 (a) a light chain variable region comprising a light chain complementary region 1 comprising the amino acids 24-39 of SEQ ID NO:9 (RSSQSIVHSNGNTYLE), a light chain complementary region 2 comprising the amino acids 55-61 of SEQ ID NO: 9 (KVSNRFS), a light chain complementary region 3 comprising amino acids 94-102 of SEQ ID NO: 9 (FGGSHVPYT); or   (b) a heavy chain variable region comprising a heavy chain complementary region 1 comprising the amino acids 30-34 of SEQ ID NO: 8 (SYGMS), a heavy chain complementary region 2 comprising the amino acids 49-65 of SEQ ID NO: 8 (TTNNNGGVTYYPDSVKG), a heavy chain complementary region 3 comprising the amino acids 98-105 SEQ ID NO: 8 (YGYYAMDY).   
     
     
         13 . The modified cell of  claim 12 , wherein the stromal cell antigen is expressed on a stromal cell present in a tumor microenvironment. 
     
     
         14 . The modified cell of  claim 12 , wherein the stromal cell antigen is fibroblast activation protein (FAP). 
     
     
         15 . The modified cell of  claim 12 , wherein the cell is a T cell. 
     
     
         16 . The modified cell of  claim 15 , wherein the T cell is an autologous T cell. 
     
     
         17 . A composition comprising the modified cell of  claim 12 . 
     
     
         18 . The composition of  claim 17 , further comprising an antitumor vaccine. 
     
     
         19 . A method of treating a tumor in a subject in need thereof, the method comprising administering to the subject an effective amount of a modified immune cell comprising a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain derived from an F19 monoclonal antibody, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain, wherein the antigen binding domain binds to a stromal cell antigen, wherein the antigen binding domain binds to a stromal cell antigen, and wherein the antigen binding domain comprises:
 (a) a light chain variable region comprising a light chain complementary region 1 comprising the amino acids 24-39 of SEQ ID NO:9 (RSSQSIVHSNGNTYLE), a light chain complementary region 2 comprising the amino acids 55-61 of SEQ ID NO: 9 (KVSNRFS), a light chain complementary region 3 comprising amino acids 94-102 of SEQ ID NO: 9 (FGGSHVPYT); or   (b) a heavy chain variable region comprising a heavy chain complementary region 1 comprising the amino acids 30-34 of SEQ ID NO: 8 (SYGMS), a heavy chain complementary region 2 comprising the amino acids 49-65 of SEQ ID NO: 8 (TTNNNGGVTYYPDSVKG), a heavy chain complementary region 3 comprising the amino acids 98-105 SEQ ID NO: 8 (YGYYAMDY).   
     
     
         20 . The method of  claim 19 , wherein the stromal cell antigen is expressed on a stromal cell present in a tumor microenvironment. 
     
     
         21 . The method of  claim 20 , wherein the tumor is a carcinoma. 
     
     
         22 . The method of  claim 19 , wherein the stromal cell antigen is fibroblast activation protein (FAP). 
     
     
         23 . The method of  claim 19 , wherein the modified cell is an autologous T cell. 
     
     
         24 . The method of  claim 19 , further comprising administering to the subject an antitumor vaccine. 
     
     
         25 . The method of  claim 24 , wherein the modified cell and the antitumor vaccine are co-administered to the subject. 
     
     
         26 . The method of  claim 24 , wherein the modified cell and the antitumor vaccine are administered to the subject separately.