Redesigned CAR-T eliminates dangerous cytokine release syndrome in lymphoma trial

Personalized CAR-T treatments for leukemia and lymphoma have offered new hope for patients with tough-to-treat disease, but the engineered cell therapies can cause a dangerous immune reaction called cytokine release syndrome (CRS). Researchers led by the University of Southern California Norris Comprehensive Cancer Center have designed a new type of CAR-T to eliminate that side effect—and they have evidence from a small human study that they’re on the right track.

The CAR-T cell therapy tested at USC caused no serious side effects in 25 lymphoma patients who received it, the university announced today. Six of the patients went into complete remissions. The study was published in the journal Nature Medicine, and the researchers are planning a phase 2 study in a larger group of patients, according to a statement.

CRS occurs when immune cells release a stream of substances into the bloodstream that cause symptoms such as fever, rash, breathing trouble and brain swelling. Because the side effects can be life-threatening, many CAR-T recipients have to be treated on an inpatient basis.

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Ever since the FDA approved two CAR-T therapies in 2017, Novartis’ Kymriah and Gilead’s Yescarta, oncology researchers have been experimenting with different methods for making the technology safer. Last year, Melbourne-based Cynata Therapeutics said it had developed mesenchymal stem cells that can tamp down CRS reactions. Scientists at the Fred Hutchinson Cancer Research Center have identified biomarkers that can predict CRS and are experimenting with different varieties and dosages of CAR-T cells.

The USC research focused on finding a safer CAR (chimeric antigen receptor) molecule than what’s used in the two CAR-T therapies that are FDA approved, both of which kill CD19-bearing cancer cells. They landed on a CAR variant called CD19-BBz(86), they explained in the study.

When T cells were transduced with CD19-BBz(86) in the lab, they produced lower levels of cytokines but maintained their ability to kill CD19 tumor cells, the USC-led team reported. CD19-BBz(86) CAR-T cells did not cause CRS in mice.

The researchers went on to test the cells at three different doses in the clinical trial. The six patients who achieved remissions received the highest dose, and five of them were still disease-free more than six months after receiving the CAR-T cells. Two additional patients in that arm of the trial experienced partial remissions. Some of the study participants did report mild side effects, but none required treatments for them, according to the authors.

"Toxicities are currently the biggest barrier to the use of CAR T-cell therapy,” said senior author Si-Yi Chen, M.D., Ph.D., professor at USC’s Keck School of Medicine. “My hope is that this safer version of CAR T cell therapy could someday be administered to patients in outpatient settings."