CAR T-Cell therapy is a form of immunotherapy that involves extracting T-Cells from blood, modifying them to express chimeric antigen receptors (CARs), and injecting them back into the bloodstream. These receptors allow T-cells to detect and kill cancer-carrying cells, making this an effective treatment for blood cancers such as B-Cell Lymphomas.
While CAR T-Cell therapy is a promising treatment option for patients that are otherwise untreatable, side-effects such as cytokine release syndrome can lead to severe complications such as hypotension and multi-organ system failure.
Normally, when cells die, they shrink and break apart. Resulting debris is then cleared up by immune cells.
Researchers at the Chinese Academy of Medical Sciences found that CAR T-cell treatment causes targeted cancer cells to rupture rather than shrinking and breaking.
This form of cell death (pyrotosis) is typically seen in infection, and causes cells to expel their contents, triggering cytokine release and inflammation.
The researchers then isolated cancer cells from patients with acute lymphoblastic leukemia and mixed them with CAR T-cells. Viewed under a microscope, the targeted cancer cells were larger and had bubbles emerging from the cell membrane. These signs are indicative of death by pyrotosis.
They also found that dying cancer cells had high levels of Gasdermin E. When this protein was blocked, cancer cells died in a less violent way. When they injected mice with cancer cells with this protein blocked and CAR T-cells, they found that symptoms of cytokine release syndrome were mild and resulted in fewer deaths overall. However, making changes to the receptors of the cancer cells also made CAR T-cells less effective against cancer cells.
Theodore Giavridis, an immunologist at ArsenalBio, who was not involved in the work believes this work is promising in the discovery of a method to prevent cytokine release syndrome in patients undergoing CAR T-cell therapy.
“It’s a great step forward. With further research, we could better dissect what are exactly the triggers … and maybe find better ways to stop inflammation from the therapy”