Treating CAR-T's toxicities

Scientists are beginning to get to the bottom of why CAR-T therapies come with such dangerous toxicities: Two Nature papers outline different mechanisms that cause cytokine release syndrome and neurotoxicity. The work is based on rudimentary mouse models, of course, but it’s still useful insight into why these potent cell therapies can be so deadly — and suggests ways these adverse events might be mitigated. The first paper pinpoints macrophages, a form of white blood cells, as the real culprits for elevated cytokine levels — not the engineered CAR-T cells themselves. Specifically, it found that two cytokines — interleukin-6, interleukin-1, and nitric oxide produced by the macrophages helped lead to the fever, hypotension, and breathing problems associated with cytokine release syndrome.

The second paper suggested that human monocytes — a form of macrophage — were likely responsible for the symptoms. The study tested two rheumatoid arthritis drugs — Actemra and Kineret — in the mice, and found that the latter, in particular, “abolished both CRS and neurotoxicity.”