Chimeric receptors with 4-1bb stimulatory signaling domain

Abstract

The present invention relates to a chimeric receptor capable of signaling both a primary and a co-stimulatory pathway, thus allowing activation of the co-stimulatory pathway without binding to the natural ligand. The cytoplasmic domain of the receptor contains a portion of the 4-1BB signaling domain. Embodiments of the invention relate to polynucleotides that encode the receptor, vectors and host cells encoding a chimeric receptor, particularly including T cells and natural killer (NK) cells and methods of use.

What is claimed is: 
     
         1 . A method of enhancing a T lymphocyte or an NK cell activity in an individual comprising introducing into the individual a T lymphocyte or NK host cell which is genetically engineered to express a chimeric receptor comprising: (a) an extracellular ligand-binding domain comprising an anti-CD19 single chain variable fragment (scFv) domain, (b) a hinge and transmembrane domain, and (c) a cytoplasmic domain comprising a 4-1BB signaling domain and a CD3ζ signaling domain. 
     
     
         2 . The method of  claim 1  wherein the 4-1BB signaling domain of the chimeric receptor comprises amino acids 214-255 of SEQ ID NO:2. 
     
     
         3 . The method of  claim 2 , wherein the hinge and transmembrane domain of the chimeric receptor is a CD8α hinge and transmembrane domain. 
     
     
         4 . The method of  claim 3 , wherein the extracellular ligand-binding domain of the chimeric receptor further comprises a signal peptide of CD8α. 
     
     
         5 . The method of  claim 1 , wherein the individual is suffering from a cancer of B-cell origin. 
     
     
         6 . The method of  claim 5 , wherein the cancer is selected from the group consisting of B-lineage acute lymphoblastic leukemia, B-cell chronic lymphocytic leukemia and B-cell non-Hodgkin's lymphoma. 
     
     
         7 . The method of  claim 5 , wherein the individual is suffering from lung cancer, melanoma, breast cancer, prostate cancer, colon cancer, renal cell carcinoma, ovarian cancer, neuroblastoma, rhabdomyosarcoma, leukemia and lymphoma, acute lymphoblastic leukemia, small cell lung cancer, Hodgkin's lymphoma, or childhood acute lymphoblastic leukemia. 
     
     
         8 . The method of  claim 1 , wherein the host cell is a T lymphocyte. 
     
     
         9 . The method of  claim 8 , wherein the T lymphocyte is an activated T lymphocyte. 
     
     
         10 . The method of  claim 8 , wherein T lymphocyte is an autologous cell isolated from a patient having a cancer of B-cell origin. 
     
     
         11 . The method of  claim 10 , wherein the autologous T lymphocyte is derived from a blood or tumor sample of a patient having a cancer of B-cell origin, and activated and expanded in vitro. 
     
     
         12 . The method of  claim 1 , wherein the host cell is an NK cell. 
     
     
         13 . The method of  claim 12 , wherein the NK cell is an allogeneic NK cell. 
     
     
         14 . The method of  claim 1 , wherein the T lymphocyte or NK host cell comprises a retroviral vector which is genetically engineered to express the chimeric receptor. 
     
     
         15 . A method for treating an individual suffering from cancer comprising introducing into the individual a T lymphocyte or an NK cell, which T lymphocyte or NK cell is genetically engineered to express a chimeric receptor comprising: (a) an extracellular ligand-binding domain comprising an anti-CD19 scFv domain; (b) a hinge region and transmembrane domain of CD8a; and (c) a cytoplasmic domain comprising a signaling domain of 4-1BB and a CD3ζ signaling domain. 
     
     
         16 . The method of  claim 15 , wherein the 4-1BB signaling domain of the chimeric receptor comprises amino acids 214-255 of SEQ ID NO:2. 
     
     
         17 . The method  claim 16 , wherein the hinge and transmembrane domain of the chimeric receptor is a CD8α hinge and transmembrane domain. 
     
     
         18 . The method of  claim 17 , wherein the extracellular ligand-binding domain of the chimeric receptor further comprises a signal peptide of CD8α. 
     
     
         19 . The method of  claim 18 , wherein the individual is suffering from a cancer of B-cell origin. 
     
     
         20 . The method of  claim 19 , wherein the cancer is selected from the group consisting of B-lineage acute lymphoblastic leukemia, B-cell chronic lymphocytic leukemia and B-cell non-Hodgkin's lymphoma. 
     
     
         21 . The method of  claim 19 , wherein the cancer is selected from the group consisting of lung cancer, melanoma, breast cancer, prostate cancer, colon cancer, renal cell carcinoma, ovarian cancer, neuroblastoma, rhabdomyosarcoma, leukemia and lymphoma, acute lymphoblastic leukemia, small cell lung cancer, Hodgkin's lymphoma, and childhood acute lymphoblastic leukemia. 
     
     
         22 . The method of  claim 15 , wherein the host cell is a T lymphocyte. 
     
     
         23 . The method of  claim 22 , wherein the T lymphocyte is an activated T lymphocyte. 
     
     
         24 . The method of  claim 15 , wherein T lymphocyte is an autologous cell isolated from a patient having a cancer of B-cell origin. 
     
     
         25 . The method of  claim 24 , wherein the autologous T lymphocyte is derived from a blood or tumor sample of a patient having a cancer of B-cell origin and activated and expanded in vitro. 
     
     
         26 . The method of  claim 15 , wherein the host cell is an NK cell. 
     
     
         27 . The method of  claim 26 , wherein the NK cell is an allogeneic NK cell. 
     
     
         28 . The method of  claim 15 , wherein the T lymphocyte or NK host cell comprises a retroviral vector which is genetically engineered to express the chimeric receptor.