Overlooked molecule might be key to how well cancer-fighting CAR-T cells work

Sharon Begley in STAT News:

A mostly overlooked component of CAR-T cells has a surprisingly strong effect on the cancer-fighting cells’ behavior, scientists reported on Tuesday, including in ways that might affect their safety and efficacy. The component is called the co-stimulatory domain, and the two CAR-T therapies approved last year to treat forms of leukemia and lymphoma — Yescarta and Kymriah — use different ones. Although the authors of the new study, in Science Signaling, are careful not to say one co-stimulatory domain is better than the other, their analyses of CAR-Ts in test tubes concluded that those with the co-stimulatory molecule CD28 attacked cancer cells more quickly and more intensely than those with the co-stimulatory molecule 4-1BB. The latter is “slower burning and more gentle,” said lead author Alex Salter of the Fred Hutchinson Cancer Research Center.

But in mice with lymphoma, they found, the 4-1BB CAR-T cleared cancer cells more effectively. The 4-1BB version also had higher expression of genes for what’s called T cell memory, which lets T cells live longer and maintain persistent anti-cancer effects.  Novartis’ Kymriah, approved for B-cell acute lymphoblastic leukemia and non-Hodgkin lymphoma, uses 4-1BB, while Gilead’s Yescarta, approved for diffuse large B cell lymphoma, uses CD28. There are no peer-reviewed studies comparing them head-to-head in patients, and in long-ago animal studies neither CD28 nor 4-1BB CAR-Ts were consistently superior to the other. The blitzkrieg behavior the scientists found with CD28 CAR-Ts might play a role in the out-of-control immune response, called cytokine release syndrome, that is a common and sometimes lethal side effect of CAR-Ts, they said. (Both Yescarta and Kymriah carry warnings about that.) The slow-and-steady behavior of 4-1BB CAR-Ts, the scientists added, might be better at preventing the relapses that some cancer patients suffer.

More here.