title: Inducible apoptosis as a safety switch for adoptive cell therapy.
abstract: BACKGROUND
  Cellular therapies could play a role in cancer treatment and regenerative medicine if it were possible to quickly eliminate the infused cells in case of adverse events. We devised an inducible T-cell safety switch that is based on the fusion of human caspase 9 to a modified human FK-binding protein, allowing conditional dimerization. When exposed to a synthetic dimerizing drug, the inducible caspase 9 (iCasp9) becomes activated and leads to the rapid death of cells expressing this construct.
  
  
  METHODS
  We tested the activity of our safety switch by introducing the gene into donor T cells given to enhance immune reconstitution in recipients of haploidentical stem-cell transplants. Patients received AP1903, an otherwise bioinert small-molecule dimerizing drug, if graft-versus-host disease (GVHD) developed. We measured the effects of AP1903 on GVHD and on the function and persistence of the cells containing the iCasp9 safety switch.
  
  
  RESULTS
  Five patients between the ages of 3 and 17 years who had undergone stem-cell transplantation for relapsed acute leukemia were treated with the genetically modified T cells. The cells were detected in peripheral blood from all five patients and increased in number over time, despite their constitutive transgene expression. A single dose of dimerizing drug, given to four patients in whom GVHD developed, eliminated more than 90% of the modified T cells within 30 minutes after administration and ended the GVHD without recurrence.
  
  
  CONCLUSIONS
  The iCasp9 cell-suicide system may increase the safety of cellular therapies and expand their clinical applications. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; ClinicalTrials.gov number, NCT00710892.).
authors: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.
authors: Antonio
authors: A
authors: Di Stasi
authors: Siok-Keen
authors: SK
authors: Tey
authors: Gianpietro
authors: G
authors: Dotti
authors: Yuriko
authors: Y
authors: Fujita
authors: Alana
authors: A
authors: Kennedy-Nasser
authors: Caridad
authors: C
authors: Martinez
authors: Karin
authors: K
authors: Straathof
authors: Enli
authors: E
authors: Liu
authors: April G
authors: AG
authors: Durett
authors: Bambi
authors: B
authors: Grilley
authors: Hao
authors: H
authors: Liu
authors: Conrad R
authors: CR
authors: Cruz
authors: Barbara
authors: B
authors: Savoldo
authors: Adrian P
authors: AP
authors: Gee
authors: John
authors: J
authors: Schindler
authors: Robert A
authors: RA
authors: Krance
authors: Helen E
authors: HE
authors: Heslop
authors: David M
authors: DM
authors: Spencer
authors: Cliona M
authors: CM
authors: Rooney
authors: Malcolm K
authors: MK
authors: Brenner
mesh_terms: D000293:Adolescent; D017209:Apoptosis; D053453:Caspase 9 / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D018014:Gene Transfer Techniques; D041722:Genes, Transgenic, Suicide; D006086:Graft vs Host Disease / Q000628:therapy*; D006801:Humans; D016219:Immunotherapy, Adoptive; D007938:Leukemia / Q000628:therapy; D008297:Male; D009930:Organic Chemicals / Q000627:therapeutic use; D012008:Recurrence; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D022021:Tacrolimus Binding Proteins / Q000235:genetics*
chemical_list: D009930:Organic Chemicals; D053453:Caspase 9; D022021:Tacrolimus Binding Proteins; C423866:AP 1903 reagent