Credit: Jim Dowdalls / Photo Researchers, Inc.

Cellular therapies—such as adoptive T cell transfer—are increasingly used to treat hematological malignancies, with encouraging results. But as progress is made in increasing the persistence and activity of the transferred T cells, the risk of serious graft-versus-host disease (GVHD) also increases. Antonio Di Stasi et al. now report their clinical test of a 'suicide gene' method to delete transferred cells and resolve GVHD in individuals receiving genetically modified T cells for the treatment of leukemia (N. Engl. J. Med. 365, 1673–1683).

Although suicide genes such as the herpes simplex virus thymidine kinase have been previously tested as a safety strategy for adoptive T cell therapies, a faster-acting alternative would be desirable. Therefore, the researchers engineered human T cells to express an inducible suicide protein consisting of human caspase 9 linked to the FK506-binding protein, FKBP12. Cells expressing this transgene are viable but rapidly undergo apoptosis when treated with the dimerizing molecule AP1903.

To test the ability of the suicide gene product to deplete engineered cells in humans, the researchers treated five individuals with leukemia with donor T cells that expressed the fusion protein. Four of the patients developed GVHD in the skin within 42 days after the transplant, and one of these individuals also developed liver GVHD. The four patients were given one dose of AP1903, and, within 30 minutes, more than 90% of the transferred T cells were eliminated from the peripheral blood, and their GVHD symptoms disappeared by 48 hours. And although some transgenic T cells persisted in the treated individuals and expanded after clearance of the dimerizing drug, GVHD did not recur within up to one year of monitoring, and three of the four individuals showed no leukemia relapse.

The results show that an inducible caspase 9 is an effective tool for the rapid and safe elimination of most transferred T cells in the advent of GVHD. The impact of such deletion of adoptively transferred T cells on cancer relapse will now require further study.