title: Serial Activation of the Inducible Caspase 9 Safety Switch After Human Stem Cell Transplantation.
abstract: Activation of the inducible caspase 9 (iC9) safety gene by a dimerizing drug (chemical inducer of dimerization (CID) AP1903) effectively resolves the symptoms and signs of graft-versus-host disease (GvHD) in haploidentical stem cell transplant (HSCT) recipients. However, after CID treatment, 1% of iC9-T cells remain and can regrow over time; although these resurgent T cells do not cause recurrent GvHD, it remains unclear whether repeat CID treatments are a safe and feasible way to further deplete residual gene-modified T cells should any other adverse effects associated with them occur. Here, we report a patient who received an infusion of haploidentical iC9-T cells after HSCT and subsequently received three treatments with AP1903. There was a mild (grade 2) and transient pancytopenia following each AP1903 administration but no non-hematological toxicity. Ninety five percent of circulating iC9-T cells (CD3(+)CD19(+)) were eliminated after the first AP1903 treatment. Three months later, the residual cells had expanded more than eightfold and had a lower level of iC9 expression. Each repeated AP1903 administration eliminated a diminishing percentage of the residual repopulating cells, but elimination could be enhanced by T-cell activation. These data support the safety and efficiency of repeated CID treatments for persistent or recurring toxicity from T-cell therapies.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Xiaoou
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Swati
authors.initials: S
authors.lastname: Naik
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Dakhova
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA.|Lineberger Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
mesh_terms: D053453:Caspase 9 / Q000235:genetics*; D002648:Child; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D041722:Genes, Transgenic, Suicide; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D009930:Organic Chemicals / Q000008:administration & dosage / Q000494:pharmacology; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000187:drug effects* / Q000637:transplantation*; D016896:Treatment Outcome
chemical_list: D009930:Organic Chemicals; C506433:CASP9 protein, human; D053453:Caspase 9; C423866:AP 1903 reagent