Safety-switch (suicide gene) CAR-T

Engineered T cells keep dividing after infusion, so a severe toxicity cannot be stopped by withholding the next dose. Safety switches add a way to remove the cells. The inducible caspase 9 (iCasp9) switch fuses human caspase 9 to a modified FK-binding protein; a bioinert dimerising drug (AP1903, later named rimiducid) activates it. In the first clinical test (Di Stasi and colleagues, Baylor College of Medicine, NEJM 2011), donor T cells carrying the switch were given to five children and young people after haploidentical stem cell transplant for relapsed acute leukaemia; in the four who developed graft-versus-host disease, a single dose of the drug eliminated more than 90 per cent of the modified T cells within 30 minutes and ended the disease without recurrence.

A second approach co-expresses a truncated EGFR (EGFRt) that has lost its signalling domain but keeps the epitope for cetuximab, so the same marker serves for selecting, tracking and, through antibody-dependent cytotoxicity, eliminating the cells (Wang and colleagues, Blood 2011). iCasp9 has been built into CAR-T products, including the GD2-CART01 cells used for relapsed neuroblastoma at Bambino Gesù, where the switch was available but not needed.