Experimental Safety Switch Has Potential to Reduce CAR T Side Effects

Investigators from UNC Lineberger Comprehensive Cancer Center have successfully incorporated an experimental safety switch into chimeric antigen receptor (CAR) T-cell therapy, reducing the severity of the treatment’s side effects in an early-phase trial.1 Their findings, which were published in the American Society of Hematology journal Blood, demonstrate a proof-of-principle with potential to expand the use of CAR T-cell therapy in conjunction with the safety switch.

CAR T-cell therapy, a type of immunotherapy that involves taking T-cells from a patient’s immune system, modifying them to prime them to attack cancer cells, then infusing them back into the patient’s blood, has picked up steam in the treatment of blood cancers since the first options were approved by the FDA in 2017. The results have been stunning, with leukemia and lymphoma patients sometimes experiencing complete remission on CAR T-cell therapy. But like most cancer therapies, it comes with a risk of side effects, some of which can be life-threatening.

Unlike with traditional oral and intravenous cancer drugs that have a dose-toxicity relationship and can be reduced to mitigate treatment toxicity, cell-based immunotherapies cannot be altered once the cells are infused with the patient’s blood. The safety switch developed by UNC Lineberger researchers, called inducible caspase-9, or iC9, is included in the engineered T-cells before infusion and can be activated with the drug rimiducid if toxic side effects develop.

In an ongoing early-phase clinical trial, researchers are working to determine whether a CAR T-cell therapy with the iC9 safety switch is safe and effective In patients with relapsed or refractory B-cell acute lymphoblastic leukemia. One of the participants, a 26-year-old woman, experienced immune effector cell-associated neurotoxicity syndrome, a severe side effect of CAR T-cell therapy. Once physicians administered rimiducid, the safety switch activated and reduced the number of modified T-cells circulating in her blood by almost 60% within 4 hours and 90% within 24 hours, eliminating the toxicities almost entirely in a single day.

"Even though this case study only documents an outcome in one patient, the fact that the drug was so successful so quickly gives us hope that it could have wider applications in a larger group of leukemia patients," said Gianpietro Dotti, MD, director of the UNC Lineberger Cellular Immunotherapy Program and professor of medicine at the UNC School of Medicine. "It should be noted that while rimiducid mitigated her toxicities, it also lowered the number of iC9 T cells fighting her cancer by 90 percent. But there seemed to be sufficient T-cells still circulating to maintain an anticancer response."

Researchers also aim to find out whether lower doses of rimiducid in patients with less severe toxicities might prevent more severe toxicities from occurring. The safety switch also might offer potential for utilizing CAR T-cells to treat solid-tumor cancers, an area where progress has been much slower.

"The ability to use a safety switch may also allow us to treat patients with solid tumors where there may be concern about the CAR-T cells affecting non-cancer tissue," Jonathan Serody, MD, director of the UNC Lineberger Cellular Therapy Program, said. "In those instances, side effects can be eliminated by activating the safety switch."

Matthew Foster, MD, lead author of the study, associate professor in the UNC School of Medicine, and a UNC Lineberger member, sees potential for even more progress in CAR T-cell therapies this year. "Given these results and the well-established high response rates in B-cell acute lymphoblastic leukemia patients receiving CAR-T cells,” he said, “it is reasonable to have a high bar in 2021 and expect that we can achieve both safety and efficacy from such therapies."

Reference

Foster MC, Savoldo B, Lau W, et al. Utility of safety switch to abrogate CD19.CAR T cell-associated neurotoxicity. Blood. Published online February 23, 2021. doi:10.1182/blood.2021010784