title: An inducible caspase 9 safety switch for T-cell therapy.
abstract: The efficacy of adoptive T-cell therapy as treatment for malignancies may be enhanced by genetic modification of infused cells. However, oncogenic events due to vector/transgene integration, and toxicities due to the infused cells themselves, have tempered enthusiasm. A safe and efficient means of removing aberrant cells in vivo would ameliorate these concerns. We describe a "safety switch" that can be stably and efficiently expressed in human T cells without impairing phenotype, function, or antigen specificity. This reagent is based on a modified human caspase 9 fused to a human FK506 binding protein (FKBP) to allow conditional dimerization using a small molecule pharmaceutical. A single 10-nM dose of synthetic dimerizer drug induces apoptosis in 99% of transduced cells selected for high transgene expression in vitro and in vivo. This system has several advantages over currently available suicide genes. First, it consists of human gene products with low potential immunogenicity. Second, administration of dimerizer drug has no effects other than the selective elimination of transduced T cells. Third, inducible caspase 9 maintains function in T cells overexpressing antiapoptotic molecules. These characteristics favor incorporation of inducible caspase 9 as a safety feature in human T-cell therapies.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Meidcine, Houston, TX 77030, USA.
authors.forename: Karin C
authors.initials: KC
authors.lastname: Straathof
authors.forename: Martin A
authors.initials: MA
authors.lastname: Pulè
authors.forename: Patricia
authors.initials: P
authors.lastname: Yotnda
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
authors.forename: Elio F
authors.initials: EF
authors.lastname: Vanin
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.forename: David M
authors.initials: DM
authors.lastname: Spencer
authors.forename: Cliona M
authors.initials: CM
authors.lastname: Rooney
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053453:Caspase 9; D020169:Caspases / Q000235:genetics* / Q000627:therapeutic use; D019281:Dimerization; D004790:Enzyme Induction; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D051379:Mice; D016688:Mice, Inbred NOD; D013601:T-Lymphocytes / Q000378:metabolism / Q000637:transplantation; D022021:Tacrolimus Binding Proteins / Q000627:therapeutic use
chemical_list: C506433:CASP9 protein, human; C506434:Casp9 protein, mouse; D053453:Caspase 9; D020169:Caspases; D022021:Tacrolimus Binding Proteins
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