Improving the safety of T-Cell therapies using an inducible caspase-9 gene

Abstract

Adoptive transfer of T cells can be an effective anticancer treatment. However, uncontrolled or unpredictable immediate or persistent toxic effects are a source of concern. The ability to conditionally eliminate aberrant cells in vivo is therefore becoming a critical step for the successful translation of this approach to the clinic. We review the evolution of safety systems, focusing on a suicide switch that can be expressed stably and efficiently 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 in the presence of an otherwise bio-inert small molecule drug. When exposed to the synthetic dimerizing drug, the inducible caspase-9 becomes activated, resulting in the rapid apoptosis of cells expressing this construct. We have illustrated the clinical feasibility and efficacy of this approach after haploidentical hematopoietic stem cell transplant. Here we review the benefits and limitations of the approach.