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.

1 - 5 . (canceled) 
     
     
         6 . A polynucleotide encoding a chimeric antigen receptor comprising: (a) an extracellular ligand-binding domain comprising an anti-CD19 single chain variable fragment (scFv) domain; (b) a transmembrane domain; and (c) a cytoplasmic domain comprising a 4-1BB signaling domain and a CD3ζ signaling domain wherein the CD3ζ signaling domain comprises the amino acid sequence of SEQ ID No. 18. 
     
     
         7 . The polynucleotide of  claim 6 , wherein the cytoplasmic domain is encoded by the nucleic acid sequence of SEQ ID No. 15. 
     
     
         8 . The polynucleotide  claim 6 , wherein the extracellular binding domain is encoded by the nucleic acid sequence of SEQ. ID. No. 9. 
     
     
         9 . The polynucleotide of  claim 6 , wherein the transmembrane domain is encoded by the nucleic acid sequence of SEQ ID No. 13. 
     
     
         10 . The polynucleotide of  claim 6 , wherein the CD3ζ signaling domain is encoded by the nucleic acid sequence of either SEQ ID No. 17. 
     
     
         11 . The polynucleotide of  claim 6  comprising the nucleotide sequence of SEQ. ID. No. 5. 
     
     
         12 . A vector comprising the polynucleotide of  claim 11 . 
     
     
         13 . The vector of  claim 12  which is a retroviral vector. 
     
     
         14 . An isolated host cell comprising the polynucleotide of  claim 11 . 
     
     
         15 . The isolated host cell of  claim 14  which is a T lymphocyte. 
     
     
         16 . The isolated host cell of  claim 14  which is an autologous cell. 
     
     
         17 . The isolated host cell of  claim 14  which is isolated from a patient having a cancer of B cell origin. 
     
     
         18 . The isolated host cell of  claim 16 , wherein the autologous cell is an autologous T lymphocyte. 
     
     
         19 . The isolated host cell of  claim 18 , 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. 
     
     
         20 . The isolated host cell of  claim 17  which is isolated from a patient having lymphoblastic leukemia, B-lineage acute lymphoblastic leukemia, B-cell chronic lymphocytic leukemia or B-cell non-Hodgkin's lymphoma. 
     
     
         21 . The isolated host cell of  claim 17 , which is isolated from a patient having 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. 
     
     
         22 . The isolated host cell of  claim 18 , 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. 
     
     
         23 - 31 . (canceled)