Methods for controlling t cell proliferation

Abstract

The technology relates generally to the field of immunology and relates in part to compositions and methods for controlling the proliferation of T cells, for example, therapeutic T cells. The methods further relate to compositions and methods for inducing an immune response in a subject.

1 - 23 . (canceled) 
     
     
         24 . A nucleic acid comprising a polynucleotide encoding a chimeric signaling molecule, wherein the chimeric signaling molecule comprises
 a) an intracellular FKBP12 polypeptide or FKBP12 variant polypeptide multimerizing region that binds to a multimeric ligand;   b) a first co-stimulatory polypeptide cytoplasmic signaling region selected from the group consisting of CD27, CD28, CD40, ICOS, 4-1BB, CD40, RANK/TRANCE-R, and OX40; and   c) a second co-stimulatory polypeptide cytoplasmic signaling region selected from the group consisting of CD27, CD28, CD40, ICOS, 4-1BB, CD40, RANK/TRANCE-R, and OX40;   wherein
 the chimeric signaling molecule lacks an extracellular domain or does not have a functional extracellular domain, and 
 the chimeric signaling molecule oligomerizes upon binding of the multimerizing region to the multimeric ligand. 
   
     
     
         25 . The nucleic acid of  claim 24 , wherein the multimeric ligand is AP1903. 
     
     
         26 . The nucleic acid of  claim 24 , wherein the FKBP12 variant polypeptide comprises a modified FKBP12 polypeptide comprising an amino acid substitution at position 36 that binds with higher affinity to AP1903 than the wild type FKBP12 polypeptide. 
     
     
         27 . The nucleic acid of  claim 26 , wherein the FKBP12 variant polypeptide comprises FKBP12v36. 
     
     
         28 . The nucleic acid of  claim 24 , wherein the multimerizing region comprises two FKBP12v36 polypeptides. 
     
     
         29 . The nucleic acid of  claim 24 , comprising a promoter sequence operably linked to the polynucleotide. 
     
     
         30 . The nucleic acid of  claim 24 , wherein the chimeric signaling molecule comprises a membrane-targeting region selected from the group consisting of myristoylation-targeting sequence, palmitoylation-targeting sequence, and prenylation sequence. 
     
     
         31 . The nucleic acid of  claim 30 , wherein the membrane-targeting region comprises a myristoylation-targeting sequence. 
     
     
         32 . The nucleic acid of  claim 24 , wherein the co-stimulatory polypeptide cytoplasmic signaling regions comprise a CD28 cytoplasmic signaling region and a 4-1BB cytoplasmic signaling region. 
     
     
         33 . A modified cell comprising a nucleic acid of  claim 24 , wherein the cell is selected from the group consisting of T cells, NK T cells, and NK cells. 
     
     
         34 . A method for making modified cell of  claim 33 , comprising transfecting or transducing a T cell, an NK T cell, or an NK cell in vitro or ex vivo with a nucleic acid comprising a polynucleotide encoding a chimeric signaling molecule, wherein the chimeric signaling molecule comprises
 a) an intracellular FKBP12 polypeptide or FKBP12 variant polypeptide multimerizing region that binds to a multimeric ligand;   b) a first co-stimulatory polypeptide cytoplasmic signaling region selected from the group consisting of CD27, CD28, CD40, ICOS, 4-1BB, CD40, RANK/TRANCE-R, and OX40; and   c) a second co-stimulatory polypeptide cytoplasmic signaling region selected from the group consisting of CD27, CD28, CD40, ICOS, 4-1BB, CD40, RANK/TRANCE-R, and OX40;   wherein
 the chimeric signaling molecule lacks an extracellular domain or does not have a functional extracellular domain, and 
 the chimeric signaling molecule oligomerizes upon binding of the multimerizing region to a multimeric ligand. 
   
     
     
         35 . A modified cell comprising a nucleic acid that comprises a polynucleotide encoding a chimeric signaling molecule, wherein:
 a) the cell is selected from the group consisting of T cells, NK T cells, and NK cells; and   b) the chimeric signaling molecule comprises
 ii) an intracellular FKBP12 polypeptide or FKBP12 variant polypeptide multimerizing region that binds to a multimeric ligand; and 
 iii) co-stimulatory polypeptide cytoplasmic signaling region selected from the group consisting of CD27, CD28, ICOS, 4-1BB, CD40, RANK/TRANCE-R, and OX40 
 wherein 
 the chimeric signaling molecule lacks an extracellular domain or does not have a functional extracellular domain, and 
 the chimeric signaling molecule oligomerizes upon binding of the multimerizing region to the multimeric ligand.