title: iCaspase 9 Suicide Gene System.
abstract: Although cellular therapies may be effective in cancer treatment, their potential for expansion, damage of normal organs, and malignant transformation is a source of concern. The ability to conditionally eliminate aberrant cells in vivo would ameliorate these concerns and broaden the application of cellular therapy. We devised an inducible T-cell safety switch that can be stably and efficiently expressed in human T cells without impairing phenotype, function, or antigen specificity. This system is based on the fusion of human caspase 9 to a modified human FK-binding protein, allowing conditional dimerization using a small-molecule drug. When exposed to a synthetic dimerizing drug, the inducible caspase 9 (iC9) becomes activated and leads to the rapid apoptosis of cells expressing this construct. We have demonstrated the clinical feasibility and efficacy of this approach after haploidentical hematopoietic stem cell transplant (haplo-HSCT). A single dose of a small-molecule drug (AP1903) eliminated more than 90 % of the modified T cells within 30 min after administration and symptoms resolved without recurrence. This system has the potential to broaden the clinical applications of cellular therapy.
authors.affiliation: Center for Cell and Gene Therapy, Texas Children's Hospital, Baylor College of Medicine, One Baylor Plaza-BCM620, Houston, TX, 77030, USA.
authors.forename: Xiaoou
authors.initials: X
authors.lastname: Zhou
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Stasi
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
mesh_terms: D017252:CD3 Complex / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D005353:Fibronectins / Q000494:pharmacology; D005434:Flow Cytometry; D041722:Genes, Transgenic, Suicide; D006801:Humans; D000922:Immunotoxins / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008212:Lymphocyte Depletion; D016853:Muromonab-CD3 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012190:Retroviridae / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014019:Tissue Donors; D014161:Transduction, Genetic; D019076:Transgenes
chemical_list: D017252:CD3 Complex; D005353:Fibronectins; D000922:Immunotoxins; D007376:Interleukin-2; D016853:Muromonab-CD3; D011994:Recombinant Proteins; C545354:retronectin; D053453:Caspase 9