Redirected cells with mhc chimeric receptors and methods of use in immunotherapy

Abstract

Chimeric receptors featuring major histocompatibility molecules grafted onto T cell receptor molecules and surrogate co-receptors featuring cell surface receptor ligands fused with signaling molecule domains. The chimeric receptors can be used to redirect cells, altering their specificity. T cells expressing chimeric receptors may bind to TCRs of target T cells for which their chimeric receptors are specific. Surrogate co-receptors may be used to help enhance TCR-CD3 signaling as part of this modular receptor system. The chimeric receptors and surrogate coreceptors may be used to help eliminate autoreactive T cells or program T cells to desired effector functions.

What is claimed is: 
     
         1 . An engineered cell, comprising:
 a. A chimeric receptor module (MHCR) that comprises: i) an extracellular domain of a major histocompatibility complex (MHC); ii) a T-cell receptor (TCR) portion comprising a transmembrane domain of a TCR, and a cytoplasmic domain of a TCR; and   b. A surrogate coreceptor (SCR) that comprises: i) an extracellular region of a cell surface receptor ligand; ii) a transmembrane region; and iii) a kinase.   
     
     
         2 . The engineered cell of  claim 1 , wherein the extracellular domain of the MHC is directly bound to the TCR portion. 
     
     
         3 . The engineered cell of  claim 1 , wherein an antigenic peptide is bound to the extracellular domain of the MHC. 
     
     
         4 . The engineered cell of  claim 1 , wherein the extracellular domain of the MHC is derived from an MHC selected from the group consisting of: HLA-A, HLA-B, HLA-C, Beta2-microglobulin, HLA-DPA, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, HLA-DRB, H2-Aa, H2-B1, H2-K1, H2-EB beta, H2-EK alpha, and H2-EK beta. 
     
     
         5 . The engineered cell of  claim 1 , wherein the transmembrane domain and the cytoplasmic domain of the TCR are derived from a TCR selected from the group consisting of: TRAC, TRBC1, TRBC2, TRDC, TRGC1, and TRGC2. 
     
     
         6 . The engineered cell of  claim 1 , wherein the cell surface receptor ligand is a T-cell surface receptor ligand. 
     
     
         7 . The engineered cell of  claim 1 , wherein the T-cell surface receptor ligand is selected from the group consisting of: a CD28 ligand, a CTLA-4 ligand, an ICOS ligand, an OX40 ligand, and a CD2 ligand. 
     
     
         8 . The engineered cell of  claim 1 , wherein the T-cell surface receptor ligand is selected from the group consisting of: CD80 and CD86. 
     
     
         9 . The engineered cell of  claim 1 , wherein the kinase is a Src kinase. 
     
     
         10 . The engineered cell of  claim 9 , wherein said Src kinase is Lck or Fyn. 
     
     
         11 . The engineered cell of  claim 6 , wherein the T-cell surface ligand is CD80, and the kinase is Lck. 
     
     
         12 . The engineered cell of  claim 6 , wherein the T-cell surface ligand is CD86, and the kinase is Lck. 
     
     
         13 . The engineered cell of  claim 1 , wherein said engineered cell is a T cell, NK cell, or NK T cell.