Deciphering a cancer treatment’s dark side

A cancer therapy that harnesses the immune system to combat tumors has come with some steep learning curves—among them, how to manage the treatment’s sometimes risky side effects. One common hazard of CAR-T cell therapy, as it’s known, is a dramatic inflammatory response, which can trigger symptoms from high fevers to organ failure. Research published today from a team of scientists in China seeks to untangle what’s happening at the cellular level during this response, in hopes of ultimately finding ways to prevent it.

CAR-T cell therapy starts when scientists genetically engineer a cancer patient’s own T cells, key sentries of the immune system, so that they target select proteins on cancer cells and destroy the cells. (CAR stands for chimeric antigen receptor, which is the introduced T cell surface protein that homes in on cancer cells.) Originally developed for blood cancers—and now approved for certain leukemias and lymphomas—the treatment is also being tested in clinical trials for a range of solid tumors. The approach has been life-saving for some advanced cancer patients, and it has inspired researchers to hunt for other immune-based treatments—and ways to make CAR-T cell therapy even more effective.

But from the earliest days, physicians and scientists saw that CAR-T cell therapy could cause a dramatic and frightening side effect, a hyperinflammatory reaction in which immune cells churn out excess molecules called cytokines that are toxic to different parts of the body, including the heart and the brain. Rates of this cytokine release syndrome (CRS) vary depending on the type of cancer that CAR-T therapy is targeting. About 90% of leukemia patients who get the treatment experience it to some degree, and CRS can be severe in about one-quarter to half of acute leukemia patients getting the immunotherapy.

With time, doctors using CAR-T cell therapy have better managed CRS, finding ways to treat it quickly without blunting the therapy’s cancer-fighting power. Still, “It would be easier to treat patients” with CAR-T therapy without CRS looming, says Saar Gill, an oncologist and cancer biologist at the University of Pennsylvania. Cutting that risk might even make CAR-T therapy possible in an outpatient setting—a game-changer for patients, who typically spend days in the hospital after receiving the immune cells, Gill says.

To decipher the dance steps of CAR-T cells and the cancer cells they chase and probe how that could lead to a flood of cytokines, researchers at the Chinese Academy of Medical Sciences (CAMS) and colleagues expose the modified immune cells to leukemia cells from patients growing in lab dishes. As expected, the CAR-T cells destroyed the cancer cells. But the interaction also prompted the CAR-T cells to release three to four times the normal quantity of two proteins, perforin and granzyme B, says tumor immunologist Bo Huang, the leader of the CAMS group. Perforin is known to punch holes in the tumor cell membrane, and granzyme B uses that access to activate another protein that punches holes in cell membranes, gasdermin E. Huang’s team observed that this chain of events initiated by CAR-T cells forced the cancer cells to swell and burst, a form of cell death known as pyroptosis. That in turn released molecules that activate immune cells called macrophages, which start to churn out the harmful cytokines behind CRS, the group reports today in Science Immunology.

Huang and his colleagues further found in mice that preventing gasdermin activation could inhibit CRS during CAR-T cell therapy. Another potential strategy is to deplete the macrophage that churn out the culprit cytokines, Huang says—that, too, worked in the mice. Ultimately, he adds, the goal is to “target CRS without hampering CAR-T killing ability.”

Doing so safely in people is still theoretical, Gill says. But the work “does shed really interesting light,” he suggests, on the interplay of immune cells and tumor cells during CAR-T cell therapy. One question for Crystal Mackall, who heads the cancer immunology and immunotherapy program at Stanford University, is whether it could give insight into neurological side effects of CAR-T therapy thought to be caused by CRS: Some patients become confused, delirious, and even stop speaking temporarily. They’re “neurologically locked in,” Mackall says. She wonders whether the new findings could help explain these neurotoxic effects—something yet to be determined.