Th1-associated micrornas and their use for tumor immunotherapy

Abstract

Described herein is the identification of miRNAs (miRs) that are up-regulated in Th1 cells compared to Th2 cells (referred to herein as Th1-associated miRs). In particular, the miR-17-92 gene cluster was found to exhibit significantly greater expression in Th1 cells. Over-expression of miR-17-92 in T cells promotes the Th1 phenotype. Thus, the use of Th1-associated miRs for cancer immunotherapy is described. Provided herein are isolated T cells containing a heterologous nucleic acid molecule encoding a Th1-associated miR, such as the miR17-92 gene cluster, or a portion thereof. Further provided is a method of treating cancer in a subject by administering to the subject an isolated T cell as disclosed herein. Also provided is a method of treating a subject with cancer by transfecting isolated T cells obtained from the subject with a heterologous nucleic acid molecule encoding a Th1-associated miR and administering the transfected T cells to the subject.

1 . A method of treating a subject with a cancer, comprising (i) selecting a subject with the cancer; and (ii) administering to the subject an isolated T cell comprising a heterologous nucleic acid molecule encoding a miR-17-92 transcript or a portion thereof, wherein the portion comprises the coding sequence for miR-17-5p, miR-17-3p, miR-18a, miR19a, miR-20a, miR19b-1 or miR-92a-1, thereby treating the subject with cancer. 
     
     
         2 . The method of  claim 1 , wherein the isolated T cell comprises a heterologous nucleic acid molecule encoding a portion of the miR-17-92 transcript, wherein the portion comprises the coding sequence for:
 (i) miR-17-5p, miR-17-3p, miR-18a and miR19a;   (ii) miR-20a, miR19b-1 and miR-92a-1; or   (iii) miR-17-5p and miR-17-3p.   
     
     
         3 . The method of  claim 1 , wherein the miR-17-92 transcript or portion thereof is a human miR-17-92 transcript or portion thereof. 
     
     
         4 . The method of  claim 1 , wherein the heterologous nucleic acid molecule comprises a vector. 
     
     
         5 . The method of  claim 4 , wherein the vector is a plasmid vector. 
     
     
         6 . The method of  claim 4 , wherein the vector is a viral vector. 
     
     
         7 . The method of  claim 6 , wherein the viral vector is a lentiviral vector. 
     
     
         8 . The method of  claim 1 , wherein the T cell administered to the subject is a tumor antigen (TA)-specific cytotoxic T lymphocyte (CTL). 
     
     
         9 . The method of  claim 8 , wherein the cancer is a glioma and the TA is a glioma-associated antigen. 
     
     
         10 . The method of  claim 1 , wherein administering to the subject the isolated T cell comprises:
 (i) isolating T cells from the subject;   (ii) transfecting the isolated T cells with a heterologous nucleic acid molecule encoding the miR-17-92 transcript or a portion thereof, wherein the portion comprises the coding sequence for miR-17-5p, miR-17-3p, miR-18a, miR19a, miR-20a, miR19b-1 or miR-92a-1; and   (iii) administering to the subject the isolated T cells transfected with the miR-17-92 transcript or portion thereof, thereby treating the subject with the cancer.   
     
     
         11 . The method of  claim 10 , wherein the isolated T cells comprise TA-specific T cells. 
     
     
         12 . The method of  claim 11 , wherein the TA is a glioma-associated antigen. 
     
     
         13 . A method of treating a subject with a cancer, comprising:
 (i) selecting a subject with the cancer;   (ii) isolating T cells from the subject;   (iii) engineering the T cells to express a chimeric antigen receptor, or an antibody or fragment thereof, that specifically binds a TA to produce isolated TA-specific T cells;   (iii) transfecting the isolated TA-specific T cells with a heterologous nucleic acid molecule encoding the miR-17-92 transcript; and   (iv) administering to the subject the isolated TA-specific T cells transfected with the miR-17-92 transcript, thereby treating the subject with the cancer.   
     
     
         14 . The method of  claim 13 , wherein the isolated TA-specific T cells are TA-specific CTLs. 
     
     
         15 . The method of  claim 13 , wherein the isolated T cells are engineered to express a chimeric antigen receptor that specifically binds the TA. 
     
     
         16 . The method of  claim 13 , wherein the isolated T cells are engineered to express an antibody or fragment thereof that specifically binds the TA. 
     
     
         17 . The method of  claim 13 , wherein the TA is a glioma-associated antigen.