Serial Activation of the Inducible Caspase 9 Safety Switch After Human Stem Cell Transplantation

Mol Ther. 2016 Apr;24(4):823-31. doi: 10.1038/mt.2015.234. Epub 2015 Dec 28.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Caspase 9 / genetics*
  • Child
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Genes, Transgenic, Suicide
  • Graft vs Host Disease / immunology
  • Graft vs Host Disease / prevention & control*
  • Hematopoietic Stem Cell Transplantation / adverse effects
  • Humans
  • Lymphocyte Activation
  • Male
  • Organic Chemicals / administration & dosage
  • Organic Chemicals / pharmacology
  • Stem Cell Transplantation
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / transplantation*
  • Treatment Outcome

Substances

  • Organic Chemicals
  • CASP9 protein, human
  • Caspase 9
  • AP 1903 reagent