Chimeric antigen receptor (CAR)-T cell therapy, which reprograms an individual's immune cells to seek out and destroy certain cancer cells, has revolutionized treatment for blood cancers such as lymphoma. But in some patients, the treatment can cause serious side effects. New research led by investigators at the Mass General Brigham Cancer Institute, the Broad Institute of MIT and Harvard, and Dana-Farber Cancer Institute has shown that patients' inherited genetic makeup can influence whether they benefit from CAR-T cell therapy or experience toxicity from the treatment. The results are published in Science Immunology.

These findings have important implications for understanding how CAR-T cells behave in patients since each CAR-T cell product is unique to the person from whom it is manufactured, unlike all prior forms of therapy, which are identical across patients."

Mark B. Leick, MD, lead author, oncologist, Mass General Brigham Cancer Institute

For the study, Leick and his colleagues sequenced the entire genomes of more than 200 patients with aggressive lymphoma from two major clinical trials of CAR-T cell therapy. In one of the trials, patients with T cells with variants that silenced the STXBP2 gene tended to experience toxicity related to CAR-T cell therapy. Also, donor T cells engineered to lack STXBP2 and/or express these STXBP2 silencing variants triggered inflammation.

In both clinical trials, variants in the ADAMTSL3 gene correlated with protection from treatment-related toxicity, and variants in the PTPN22 gene were strongly associated with enhanced CAR T-cell expansion, which correlates with effective therapy.

The results suggest that variants in these different genes can shape the safety and therapeutic activity of CAR-T cell and other immune cell therapies.

"This may have implications for identifying the right donor for CAR-T cells, where a single donor can provide T cells for hundreds of patients, and for the design of augmented CAR-T cells, based on a deeper understanding of how human genetic variation impacts CAR-T cell behavior," said co-senior author Marcela Maus, MD, PhD, the Paula J. O'Keeffe Endowed Chair of the Mass General Brigham Cancer Institute and the Director of the Cellular Immunotherapy Program.