Compositions and methods for immunotherapy

Abstract

The present invention provides for methods and compositions for enhancing the immune response toward cancers and pathogens. It relates to immunoresponsive cells bearing antigen receptors, which can be chimeric antigen receptors (CARs), which express introduced ligands for immunomodulatory molecules. In particular embodiments, engineered immunoresponsive cells are antigen-directed and resist immunosuppression and/or have enhances immune-activating properties.

What is claimed is: 
     
         1 . An immunoresponsive cell comprising:
 a) an antigen recognizing receptor that binds an antigen, wherein the binding activates the immunoresponsive cell, and   b) a soluble single-chain variable fragment (scFv) that binds a polypeptide that has immunosuppressive activity or immunostimulatory activity.   
     
     
         2 . The immunoresponsive cell of  claim 1 , wherein the soluble scFv is secreted. 
     
     
         3 . The immunoresponsive cell of  claim 1 , wherein the antigen recognizing receptor and/or the soluble scFv is recombinantly expressed or expressed from a vector. 
     
     
         4 . The immunoresponsive cell of  claim 1 , wherein the cell is selected from the group consisting of a T cell, a Natural Killer (NK) cell, and a pluripotent stem cell from which a lymphoid cell may be differentiated. 
     
     
         5 . The immunoresponsive cell of  claim 1 , wherein the immunoresponsive cell is a T cell. 
     
     
         6 . The immunoresponsive cell of  claim 5 , wherein the T cell is a cytotoxic T lymphocyte (CTL) or a regulatory T cell. 
     
     
         7 . The immunoresponsive cell of  claim 1 , wherein the antigen is a tumor antigen or a pathogen antigen. 
     
     
         8 . The immunoresponsive cell of  claim 1 , wherein the antigen is a tumor antigen. 
     
     
         9 . The immunoresponsive cell of  claim 8 , wherein the tumor antigen is selected from the group consisting of CD19, MUC16, MUC1, CAIX, CEA, CD S, CD7, CD10, CD20, CD22, CD30, CD33, CD34, CD38, CD41, CD44, CD49f, CD56, CD74, CD133, CD138, a cytomegalovirus (CMV) infected cell antigen, EGP-2, EGP-40, EpCAM, Erb-B2, Erb-B3, Erb-B4, FBP, Fetal acetylcholine receptor, folate receptor-α, GD2, GD3, HER-2, hTERT, IL-13R-α2, K-light chain, KDR, LeY, L1 cell adhesion molecule, MAGE-A1, Mesothelin, NKG2D ligands, NY-ESO-1, oncofetal antigen (h5T4), PSCA, PSMA, ROR1, TAG-72, VEGF-R2, and WT-1. 
     
     
         10 . The immunoresponsive cell of  claim 1 , wherein the antigen is CD19 or MUC16. 
     
     
         11 . The immunoresponsive cell of  claim 1 , wherein the immunosuppressive polypeptide is selected from the group consisting of CD47, PD-1, CTLA-4, and ligands thereof. 
     
     
         12 . The immunoresponsive cell of  claim 1 , wherein the immunostimulatory polypeptide is selected from the group consisting of CD28, OX-40, 4-1B13, and ligands thereof. 
     
     
         13 . The immunoresponsive cell of  claim 1 , wherein the antigen recognizing receptor is a T cell receptor (TCR) or chimeric antigen receptor (CAR). 
     
     
         14 . The immunoresponsive cell of  claim 1 , wherein the antigen recognizing receptor is a chimeric antigen receptor (CAR). 
     
     
         15 . The immunoresponsive cell of  claim 1 , wherein the CAR comprises an intracellular signaling domain. 
     
     
         16 . The immunoresponsive cell of  claim 15 , wherein the intracellular signaling domain comprises a CD3-chain. 
     
     
         17 . The immunoresponsive cell of  claim 15 , wherein the intracellular signaling domain comprises a signaling domain of 4-1BB, a signaling domain of CD28 signaling domain, a signaling domain of CD97, a signaling domain of CD11a-CD18, a signaling domain of CD2, a signaling domain of ICOS, a signaling domain of CD27, a signaling domain of CD154, a signaling domain of CDS, a signaling domain of OX40, or a combination thereof. 
     
     
         18 . The immunoresponsive cell of  claim 15 , wherein the intracellular signaling domain comprises a signaling domain of 4-1BB or a signaling domain of CD28. 
     
     
         19 . A pharmaceutical composition comprising an effective amount of an immunoresponsive cell of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         20 . A kit for treatment of a tumor, a pathogen infection, or an autoimmune disorder, the kit comprising an immunoresponsive cell of  claim 1 .