Blocking a protein makes cells shrink instead, causing fewer problems

Techniques to genetically modify patient immune cells have revolutionized the fight against hard-to-treat cancers. But they can come with dangerous side effects. Now, researchers have found one reason why.

A particularly messy form of cell death sparks severe inflammation in patients receiving CAR-T cell immunotherapy for blood cancers, researchers report January 17 in Science Immunology.

This treatment, approved for certain patients with acute lymphoblastic leukemia and non-Hodgkin’s lymphoma (SN: 12/13/17), unleashes immune cells in a patient’s bloodstream, tweaked to produce artificial proteins called chimeric antigen receptors, or CAR. The proteins prime T cells to recognize cancer cells so that the immune cells can hunt down and kill the rogue cells.

Normally as cells die, they shrink and break apart — a highly controlled process whose debris is easily vacuumed up by the body’s natural defenses. During CAR-T cell treatment, however, targeted cancer cells can swell and rupture in a manner typically associated with infection, Bo Huang, an immunologist at the Chinese Academy of Medical Sciences in Beijing, and colleagues found. This explosive cell death, or pyroptosis, causes dead cells to expel their contents. That, in turn, prompts the immune system to produce cytokine chemicals that trigger inflammation.

Cytokine release syndrome, one of the most common side effects for CAR-T cell therapy patients (SN: 6/27/18), can cause high fever, rapid heartbeat and multi-organ failure. Although most people survive, some require intensive care. Until now, scientists didn’t know what triggered the syndrome. Pinpointing the root cause could help researchers find ways to stop the onslaught of inflammation, Huang says.

Huang and his colleagues mixed cancer cells isolated from patients with acute lymphoblastic leukemia with CAR-T cells in a flask and looked for signs of cell death. Under a microscope, doomed cancer cells looked swollen. Bubbles protruded from holes on the cell’s surface — evidence of death by pyroptosis.

Dying cells had high levels of a cellular protein called gasdermin E, or GSDME, which punctures the cell membrane, the team found. Nearby immune cells picked up on distress signals from the exploded cell and released cytokines that set off inflammation, Huang says.

When GSDME was blocked, the cancer cells succumbed in a less messy way: They probably wilted instead of exploding, causing less damage, the team found. Mice injected with CAR-T cells and cancer cells lacking this protein still had symptoms of cytokine release syndrome, Huang says, but the symptoms were mild and fewer mice died.

The results hint at a starting point to find a way to reduce severe side effects of CAR-T cell therapy, although treatments for people are probably far off. One approach might be to block GSDME to ensure cancer cells die without producing distress signals, Huang says. Another is to find ways to prevent other parts of the immune system from responding when edited T cells attack cancer cells, but that could leave patients vulnerable to infection.

“It’s a great step forward,” says Theodore Giavridis, an immunologist and cellular engineer at ArsenalBio, a precision immunotherapy company in San Francisco, who was not involved in the work. If the findings hold up, they would boost understanding of cytokine release syndrome. But it’s possible that blocking pyroptosis from happening at all will make CAR-T cells less effective, Giavridis says. “With further research, we could better dissect what are exactly the triggers … and maybe find better ways” to stop inflammation from the therapy, he says.