Method and compositions for cellular immunotherapy

Abstract

The present invention provides nucleic acids, vectors, host cells, methods and compositions to confer and/or augment immune responses mediated by cellular immunotherapy, such as by adoptively transferring CD8+ central memory T cells or combinations of central memory T cells with CD4+ T cells that are genetically modified to express a chimeric receptor. In some alternatives the genetically modified host cell comprises a nucleic acid comprising a polynucleotide coding for a ligand binding domain, a polynucleotide comprising a customized spacer region, a polynucleotide comprising a transmembrane domain, and a polynucleotide comprising an intracellular signaling domain. In some alternatives, the ligand binding domains binds to CD171.

1 .- 31 . (canceled) 
     
     
         32 . A chimeric receptor encoded by a nucleic acid comprising:
 (a) a polynucleotide encoding a ligand binding domain, wherein the ligand binding domain is capable of specifically binding to CD171;   (b) a polynucleotide encoding a spacer, wherein the spacer has a length less than or equal to 119 consecutive amino acids;   (c) a polynucleotide encoding a transmembrane domain; and   (d) a polynucleotide encoding an intracellular signaling domain.   
     
     
         33 . The chimeric receptor of  claim 32 , wherein the polynucleotide encoding the ligand binding domain comprises the nucleotide sequence of residues 2150 to 2875 set forth in SEQ ID NO:54. 
     
     
         34 . The chimeric receptor of  claim 32 , wherein the spacer has a length greater than or equal to 12 consecutive amino acids. 
     
     
         35 . The chimeric receptor of  claim 32 , wherein the spacer has a length greater than or equal to 12 and less than or equal to 15 consecutive amino acids. 
     
     
         36 . The chimeric receptor of  claim 32 , wherein the spacer comprises the amino acid sequence set forth in SEQ ID NO:01. 
     
     
         37 . The chimeric receptor of  claim 32 , wherein the spacer comprises the amino acid sequence set forth in SEQ ID NO:21. 
     
     
         38 . The chimeric receptor of  claim 32 , wherein the spacer comprises the amino acid sequence set forth in SEQ ID NO:59. 
     
     
         39 . The chimeric receptor of  claim 32 , wherein the intracellular signaling domain comprises all of or a portion of a CD3 zeta domain in combination with a costimulatory domain selected from the group consisting of CD27, CD28, 4-1BB, OX-40, CD30, CD40, PD-1, ICOS, LFA-1, CD2, CD7, NKG2C, B7-H3, and a combination thereof. 
     
     
         40 . The chimeric receptor of  claim 32 , wherein the intracellular signaling domain comprises all or a portion of a CD3 zeta domain and all or a portion of a 4-1BB costimulatory domain. 
     
     
         41 . The chimeric receptor of  claim 32 , wherein the nucleic acid comprises at least 95% sequence identity to the nucleotide sequence set forth in SEQ ID NO:55 or SEQ ID NO:56. 
     
     
         42 . A method of performing cellular immunotherapy in a subject having a cancer comprising:
 administering a cell to the subject, wherein the cell comprises the chimeric receptor of  claim 32 .   
     
     
         43 . The method of  claim 42 , wherein the cell is selected from the group consisting of a CD4+ T cell, a CD8+ T cell, a hematopoietic stem cell, and a precursor T cell. 
     
     
         44 . The method of  claim 42 , wherein the cell is a CD4+ T helper cell selected from the group consisting of a naïve CD4+ T cell, a central memory CD4+ T cell, an effector memory CD4+ T cell, and a bulk CD4+ T cell. 
     
     
         45 . The method of  claim 42 , wherein the cell is a CD8+ cytotoxic T cell selected from the group consisting of a naïve CD8+ T cell, a central memory CD8+ T cell, an effector memory CD8+ T cell, and a bulk CD8+ T cell. 
     
     
         46 . The method of  claim 42 , wherein the cancer expresses CD171. 
     
     
         47 . The method of  claim 42 , wherein the cancer is selected from the group consisting of a breast cancer, a brain cancer, a colon cancer, a renal cancer, a pancreatic cancer, a uterine cancer, a cervical cancer, an ovarian cancer, a glioblastoma, and a melanoma. 
     
     
         48 . The method of  claim 42 , wherein the cancer comprises a neuroblastoma. 
     
     
         49 . The method of  claim 42 , wherein the cell is autologous to the subject. 
     
     
         50 . The method of  claim 42 , wherein the cell is allogeneic to the subject. 
     
     
         51 . The method of  claim 42 , wherein the subject is human.