Pd1-specific chimeric antigen receptor as an immunotherapy

Abstract

Provided herein are methods and compositions useful for treating PDL1 and/or PDL2 positive cancers through adoptive cell transfer of T cells genetically engineered to express a PDI-specific chimeric antigen receptor, Co-stimulatory domains such as Dap 10 may be included to enhance efficacy.

1 . A chimeric antigen receptor (CAR) polypeptide comprising:
 a programmed death receptor 1 (PDI) extracellular domain;   a transmembrane domain; a CD3ζ cytoplasmic domain; and a DNAX-activating protein 10 (Dap10) co-stimulatory domain.   
     
     
         2 - 5 . (canceled) 
     
     
         6 . A vector comprising a nucleic acid encoding the CAR polypeptide according to  claim 1 . 
     
     
         7 . A T lymphocyte genetically modified to express a CAR according to  claim 1 . 
     
     
         8 . A composition for adoptive cell transfer comprising T lymphocytes according to  claim 7  and a pharmaceutically acceptable carrier. 
     
     
         9 . The composition of  claim 8 , further comprising one or more chemotherapeutic or radiotherapeutic agents. 
     
     
         10 . A method of treating cancer in a subject in need thereof, wherein cells of said cancer express at least one of PDL1 and PDL2, comprising: administering to the subject a therapeutically effective amount of a composition for adoptive cell transfer comprising T lymphocytes comprising a polynucleotide encoding the CAR polypeptide of  claim 1 . 
     
     
         11 - 14 . (canceled) 
     
     
         15 . The method of  claim 10 , wherein said cancer is selected from the group consisting of lymphoma, melanoma, myeloma, pancreatic cancer, breast cancer, and ovarian cancer, prostate cancer, brain cancer, liver cancer, kidney cancer, lung cancer, spleen cancer, gall bladder cancer, anal cancer, testicular cancer, ovarian cancer, cervical cancer, skin cancer, bone cancer, and colon cancer. 
     
     
         16 . The method of  claim 10 , further comprising a step of administering one or more of a chemotherapeutic or radiotherapeutic agent. 
     
     
         17 . The CAR polypeptide of  claim 1 , wherein said transmembrane domain is a T-cell receptor alpha chain, a T-cell receptor beta chain, a CD3 zeta chain, CD28, CD3s, CD45, CD4, CDS, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, ICOS, CD154, a functional derivative thereof, or a combination thereof. 
     
     
         18 . The CAR polypeptide of  claim 1 , wherein said transmembrane domain is an artificial transmembrane domain. 
     
     
         19 . The method of  claim 10 , wherein said transmembrane domain is a T-cell receptor alpha chain, a T-cell receptor beta chain, a CD3 zeta chain, CD28, CD3s, CD45, CD4, CDS, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, ICOS, CD154, a functional derivative thereof, or a combination thereof. 
     
     
         20 . The method of  claim 10 , wherein said transmembrane domain is an artificial transmembrane domain. 
     
     
         21 . The vector of  claim 6 , wherein said vector is a viral vector. 
     
     
         22 . The vector of  claim 21 , wherein said viral vector is an adenoviral vector, an adeno-associated virus vector, a retroviral vectors, or a lentiviral vector. 
     
     
         23 . The method of  claim 16 , wherein administration of said composition for adoptive cell transfer and said one or more of a chemotherapeutic or radiotherapeutic agent are administered sequentially. 
     
     
         24 . The method of  claim 10 , further comprising administration of Cytokine Release Syndrome (CRS) therapy. 
     
     
         25 . The method of  claim 10 , wherein said cancer is metastatic cancer. 
     
     
         26 . A kit for cell therapy comprising a composition of T lymphocytes genetically modified to express a CAR according to  claim 1  in a pharmaceutically acceptable form, said composition in a suitable container.