CAR-T Cell Therapies Impacted by Exploding Cancer Cells

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. 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. 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, 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.

CITATIONS Y. Liu et al. Gasdermin E-mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome. Science Immunology. Vol. 5, January 17, 2020. doi: 10.1126/sciimmunol.aax7969.