Chimeric antigen receptor (CAR)-T cell therapy, which reprograms an individual’s immune cells to seek out and destroy specific cancer cells, has revolutionized the treatment of blood cancers such as lymphoma. However, for some patients, this treatment can cause serious side effects. A new study led by researchers at the Massachusetts General Brigham Cancer Institute, the Broad Institute of Massachusetts Institute of Technology and Harvard University, and the Dana-Farber Cancer Institute shows that a patient’s genetic genetic makeup can influence whether they benefit from CAR T-cell therapy or experience toxicity from the treatment. The result is scientific immunology.
“These findings have important implications for understanding how CAR-T cells behave in a patient’s body, because each CAR-T cell product is unique to the person for whom it is manufactured, unlike all conventional treatments, which are the same from patient to patient,” said lead author Mark B. Reich, M.D., an oncologist at Massachusetts General Brigham Cancer Institute.
For this study, Leick and colleagues sequenced the whole genomes of more than 200 lymphoma patients from two major clinical trials of CAR T-cell therapy. In one study, patients with T-cell mutations that suppressed their ability to STXBP2 Gene was more likely to experience toxicity associated with CAR-T cell therapy. Additionally, donor T cells are engineered to be defective. STXBP2 and/or express these STXBP2 be silent The mutant caused inflammation.
In both clinical trials, ADAMTSL3 Genes and their variants that correlate with protection from treatment-related toxicity PTPN22 The gene is strongly associated with enhanced CAR T cell proliferation, which correlates with effective therapy.
The results suggest that variants in these different genes may shape the safety and therapeutic activity of CAR-T cells and other immune cell therapies.
“This is based on identifying suitable donors for CAR-T cells (a single donor can provide T cells for hundreds of patients) and on our deep understanding of how human genetic variation affects CAR-T cell behavior. This could potentially impact the design of AR-T cells,” said co-senior author Marcella Maus, M.D., Ph.D., Paula J. O’Keefe Endowed Chair and Director of the Cellular Division at Massachusetts General Brigham Cancer Institute. Immunotherapy program.
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DOI: 10.1126/scimmunol.aef4134
