Methods for inducing selective apoptosis

Abstract

Provided herein are methods for cell therapy by modifying transfused cells to express an inducible caspase 9 protein, so that the cells may be selectively killed if the patient experiences dangerous side effects. Provided also within relates in part to methods for preventing or treating Graft versus Host Disease by modifying T cells before administration to a patient, so that they may be selectively killed if GvHD develops in the patient.

1 - 23 . (canceled) 
     
     
         24 . A method of controlling the survival of therapeutic cells in a human patient, comprising administering a multimeric ligand to a human patient to whom therapeutic cells have been administered, wherein:
 the therapeutic cells have been transfected or transduced with a nucleic acid comprising (i) a promoter region, and (ii) a polynucleotide that encodes a chimeric protein comprising a multimeric ligand binding region and a caspase-9 polypeptide;   the promoter region is operatively linked to the polynucleotide;   the multimeric ligand binds to the multimeric ligand binding region;   the multimeric ligand binding region comprises an FKBP12 polypeptide;   the number of therapeutic cells that express the caspase-9 polypeptide is reduced at least 90% within 24 hours following administration of the multimeric ligand.   
     
     
         25 . The method of  claim 24 , wherein therapeutic cells that are not undergoing cell division are killed following administration of the multimeric ligand. 
     
     
         26 . The method of  claim 24 , wherein the number of therapeutic cells is reduced at least 90% within 30 minutes following administration of the multimeric ligand. 
     
     
         27 . The method of  claim 24 , wherein the therapeutic cells are non-allodepleted. 
     
     
         28 . The method of  claim 24 , wherein the therapeutic cells comprise allogeneic T cells. 
     
     
         29 . The method of  claim 24 , wherein the therapeutic cells comprise polyclonal T cells. 
     
     
         30 . The method of  claim 24 , wherein the therapeutic cells comprise cytotoxic T cells. 
     
     
         31 . The method of  claim 24 , wherein the therapeutic cells comprise T cells reactive to tumor cells in the patient. 
     
     
         32 . The method of  claim 24 , wherein the therapeutic cells comprise tumor-associated antigen specific T cells. 
     
     
         33 . The method of  claim 24 , wherein the therapeutic cells comprise virus-specific T cells. 
     
     
         34 . The method of  claim 24 , further comprising administering a haploidentical stem cell transplant to the patient. 
     
     
         35 . The method of  claim 24 , wherein the caspase-9 polypeptide is a truncated caspase-9 polypeptide. 
     
     
         36 . The method of  claim 24 , wherein the chimeric protein further comprises a marker polypeptide. 
     
     
         37 . The method of  claim 24 , wherein the FKBP12 polypeptide is encoded by a wobbled nucleotide sequence. 
     
     
         38 . The method of  claim 24 , comprising administering a composition comprising the therapeutic cells to the patient prior to administering the multimeric ligand to the patient. 
     
     
         39 . The method of  claim 38 , wherein the therapeutic cells comprise allogeneic T cells. 
     
     
         40 . The method of  claim 39 , wherein the allogeneic T cells are not in an active state when administered to the patient. 
     
     
         41 . The method of  claim 39 , wherein the composition comprising the allogeneic T cells is over 90% pure.