New research led by investigators at the Mass General Brigham Cancer Institute, the Broad Institute of MIT and Harvard, and Dana-Farber Cancer Institute shows that inherited genetic makeup can influence both the benefits and risks associated with chimeric antigen receptor (CAR)-T cell therapy. The findings were published in Science Immunology, according to a July 24 announcement.
Lead author Mark B. Leick, MD, an oncologist at the Mass General Brigham Cancer Institute, said, "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."
For their study, Leick and colleagues sequenced entire genomes from more than 200 patients with aggressive lymphoma who participated in two major clinical trials involving CAR-T cell therapy. In one trial, they found that patients whose T cells had variants silencing the STXBP2 gene tended to experience toxicity related to CAR-T treatment. Additionally, donor T cells engineered to lack STXBP2 or express these silencing variants triggered inflammation.
The research also found that in both clinical trials, variants in the ADAMTSL3 gene correlated with protection against treatment-related toxicity. Meanwhile, variants in another gene—PTPN22—were strongly associated with increased expansion of CAR T-cells after infusion into patients' bodies; this expansion correlates with more effective therapy.
The results suggest that differences in genes such as STXBP2, ADAMTSL3, and PTPN22 can shape both safety profiles and therapeutic activity for recipients of CAR-T cell or other immune-based therapies. Co-senior author Marcela Maus, MD, PhD, said, "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."
