Major finding: Inducible caspase 9 safely and rapidly eliminates donor T cells in patients.
Concept: Synthetic drug-induced dimerization of caspase 9 triggers apoptosis.
Impact: The iCasp9 system may improve the safety of cell-based therapies.
Although adoptive transfer of genetically modified T cells has been used successfully to treat a number of malignancies, it carries potential risks, including direct toxicity, uncontrolled expansion, and malignant transformation secondary to insertional mutagenesis. Inclusion of a suicide gene, or safety switch, which can be triggered in the case of an adverse event, may circumvent these risks. A widely used suicide gene, the herpes simplex virus I thymidine kinase, is immunogenic and slow to initiate cell death, and consequently the clinically important antiviral agent ganciclovir is required along with the cell-based therapy. Therefore, Di Stasi and colleagues tested an alternative cell-suicide system that is based on induction of the proapoptotic protein caspase 9 in 5 patients with relapsed acute leukemia following allogeneic stem-cell transplant. The inducible caspase 9 transgene (iCasp9) contains human caspase 9 fused to an FK-binding protein variant that binds the synthetic dimerizing agent AP1903. In the presence of drug, iCasp9 dimerizes, activates the intrinsic apoptotic pathway, and rapidly promotes cell death. After patient transfer, the iCasp9-transduced T cells successfully expanded in vivo but caused graft-versus-host disease (GVHD) in 4 of the 5 recipients. Impressively, a single infusion of AP1903 eliminated more than 90% of circulating transgenic T cells within 30 minutes, leading to complete resolution of the GVHD, even 1 year later. The apparent benefits of the iCasp9 system are lower immunogenicity, activation by a bioinert small molecule, rapid onset, and relatively long-lasting effects. Together, these observations suggest that iCasp9 may improve the safety of cell-based therapies and should encourage its application in additional clinical settings.
Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med 201;365:1673–83.
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