iCaspase 9 suicide gene system

Xiaoou Zhou, Antonio Di Stasi, Malcolm K. Brenner

Research output: Contribution to journalArticle

11 Scopus citations

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 effi ciently expressed in human T cells without impairing phenotype, function, or antigen specifi city. This system is based on the fusion of human caspase 9 to a modifi ed human FK-binding protein, allowing conditional dimerization using a smallmolecule 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 effi cacy 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 modifi ed 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.

Original languageEnglish (US)
Pages (from-to)87-105
Number of pages19
JournalMethods in Molecular Biology
Volume1317
DOIs
StatePublished - 2015

Keywords

  • AP1903
  • Allodepleted T cells
  • Dimerizer
  • GvHD
  • Inducible caspase 9
  • Safety switch
  • Suicide gene

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics

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