[HTML][HTML] Inducible apoptosis as a safety switch for adoptive cell therapy
A Di Stasi, SK Tey, G Dotti, Y Fujita… - … England Journal of …, 2011 - Mass Medical Soc
New England Journal of Medicine, 2011•Mass Medical Soc
Background Cellular therapies could play a role in cancer treatment and regenerative
medicine if it were possible to quickly eliminate the infused cells in case of adverse events.
We devised an inducible T-cell safety switch that is based on the fusion of human caspase 9
to a modified human FK-binding protein, allowing conditional dimerization. When exposed
to a synthetic dimerizing drug, the inducible caspase 9 (iCasp9) becomes activated and
leads to the rapid death of cells expressing this construct. Methods We tested the activity of …
medicine if it were possible to quickly eliminate the infused cells in case of adverse events.
We devised an inducible T-cell safety switch that is based on the fusion of human caspase 9
to a modified human FK-binding protein, allowing conditional dimerization. When exposed
to a synthetic dimerizing drug, the inducible caspase 9 (iCasp9) becomes activated and
leads to the rapid death of cells expressing this construct. Methods We tested the activity of …
Background
Cellular therapies could play a role in cancer treatment and regenerative medicine if it were possible to quickly eliminate the infused cells in case of adverse events. We devised an inducible T-cell safety switch that is based on the fusion of human caspase 9 to a modified human FK-binding protein, allowing conditional dimerization. When exposed to a synthetic dimerizing drug, the inducible caspase 9 (iCasp9) becomes activated and leads to the rapid death of cells expressing this construct.
Methods
We tested the activity of our safety switch by introducing the gene into donor T cells given to enhance immune reconstitution in recipients of haploidentical stem-cell transplants. Patients received AP1903, an otherwise bioinert small-molecule dimerizing drug, if graft-versus-host disease (GVHD) developed. We measured the effects of AP1903 on GVHD and on the function and persistence of the cells containing the iCasp9 safety switch.
Results
Five patients between the ages of 3 and 17 years who had undergone stem-cell transplantation for relapsed acute leukemia were treated with the genetically modified T cells. The cells were detected in peripheral blood from all five patients and increased in number over time, despite their constitutive transgene expression. A single dose of dimerizing drug, given to four patients in whom GVHD developed, eliminated more than 90% of the modified T cells within 30 minutes after administration and ended the GVHD without recurrence.
Conclusions
The iCasp9 cell-suicide system may increase the safety of cellular therapies and expand their clinical applications. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; ClinicalTrials.gov number, NCT00710892.)
The New England Journal Of Medicine