Methods of treating cancer in a subject by administering a composition comprising gamma 9 delta 2 t-cell receptors

Abstract

The current invention provides methods to identify γ9δ2T-cell receptors (γ9δ2TCR) that mediate anti-tumour responses. Surprisingly, it was now found that the CDR3 regions of the γ9-T-cell receptor chain and the δ2-T-Cell receptor chain (δ2TCR chain) are of importance. Based on these findings, combinatorial-γδTCR-chain-exchange (CTE) is proposed as an efficient method for identifying γ9δ2TCRs that mediate anti-tumour responses. Using the method of the invention, specific sequences of the respective γ9TCR and δ2TCR chains were identified that mediate anti-tumour responses. Hence, the invention further provides for specific γ9δ2TCRs, or fragments thereof, that may be used e.g. in diagnostics or treatment of cancer. The invention further provides for nucleic acid sequences, genetic constructs and retroviral vectors that can be used to express the γ9δ2TCRs according to the invention.

1 . A composition comprising an engineered αβ T-cell that expresses an exogenous γ9δ2T-cell receptor or a functional fragment thereof, wherein said γ9δ2T-cell receptor or the functional fragment thereof increases the avidity of the engineered αβ T-cell to a cancer cell compared to a non-engineered αβ T-cell. 
     
     
         2 . The composition of  claim 1 , wherein the engineered αβ T-cell comprises a nucleic acid encoding the γ9δ2T-cell receptor sequence or the functional fragment thereof. 
     
     
         3 . The composition of  claim 1 , wherein said engineered cell is modified at an αβ T-cell receptor (TCR) locus. 
     
     
         4 . The composition of  claim 3 , wherein said modification results in a downregulation of expression of an endogenous αβ TCR in said engineered cell as compared to an expression of said endogenous αβ TCR in a comparable non-engineered cell. 
     
     
         5 . The composition of  claim 1 , wherein said cancer cell is a hematological cancer cell or a solid cancer cell. 
     
     
         6 . The composition of  claim 1 , wherein said cancer cell is a cancer cell selected from the group consisting of multiple myeloma, Acute Myeloid Leukemia (AML), and myelogenous leukemia. 
     
     
         7 . The composition of  claim 1 , wherein said cancer cell is a cancer cell selected from the group consisting of osteosarcoma, renal cell carcinoma, head and neck cancer, breast cancer, glioblastoma, and colon carcinoma. 
     
     
         8 . The composition of  claim 1 , further comprising an engineered progenitor cell, wherein said engineered progenitor cell comprises said γ9δ2T-cell receptor. 
     
     
         9 . (canceled) 
     
     
         10 . The cellular composition of  claim 8 , wherein said engineered progenitor cell is a thymocyte or a blood stem cell. 
     
     
         11 . The composition of  claim 1 , wherein said γ9δ2T-cell receptor binds to an antigen expressed on the surface of a cancer cell. 
     
     
         12 . The composition of  claim 1 , wherein said engineered αβ T-cell is a CD8+ T-cell or a CD4+ T-cell. 
     
     
         13 . A pharmaceutical composition comprising an engineered αβ T-cell that comprises an exogenous γ9δ2T-cell receptor, and a pharmaceutically acceptable adjuvant, carrier or diluent. 
     
     
         14 . The pharmaceutical composition of  claim 13 , comprising an engineered αβ T-cell, wherein the engineered αβ T-cell comprises a nucleic acid sequence encoding the γ9δ2T-cell receptor sequence or the functional fragment thereof. 
     
     
         15 . (canceled) 
     
     
         16 . The pharmaceutical composition of  claim 13 , wherein said engineered αβ T-cell is a CD8+ T-cell or a CD4+ T-cell. 
     
     
         17 . A method for treating a cancer in a subject in need thereof, the method comprising: administering to the subject a pharmaceutical composition comprising an engineered αβ T-cell that expresses an exogenous γ9δ2T-cell receptor of a functional fragment thereof. 
     
     
         18 - 19 . (canceled) 
     
     
         20 . The method of  claim 17 , wherein the pharmaceutical composition comprising the engineered αβ T-cell is administered intravenously to the subject. 
     
     
         21 . The method of  claim 17 , wherein administering the pharmaceutical composition comprising said engineered cell results in reduction in cancer growth. 
     
     
         22 - 23 . (canceled) 
     
     
         24 . A method of making the composition of  claim 1 , the method comprising: engineering an αβ T-cell to express an exogenous γ5T cell receptor or a fragment thereof, having a γ9TCR chain and a δ2TCR chain or functional fragments thereof, and wherein the engineered cell has increased avidity to a cancer cell expressing an antigen capable of being bound by an antigen binding domain of the γ9TCR chain and δ2TCR chain. 
     
     
         25 - 26 . (canceled) 
     
     
         27 . The method of  claim 24 , wherein the engineering an αβ T-cell comprises modifying an αβ T-cell receptor (TCR) locus, such that the modification results in a downregulation of expression of an endogenous αβ TCR in said engineered cell as compared to an expression of said endogenous αβ TCR in a comparable non-engineered αβ T-cell. 
     
     
         28 . The method of  claim 24 , wherein said cancer cell is selected from the group consisting of multiple myeloma, Acute Myeloid Leukemia (AML), myelogenous leukemia, osteosarcoma, renal cell carcinoma, head and neck cancer, breast cancer, glioblastoma, and colon carcinoma. 
     
     
         29 - 30 . (canceled)