Scientists have identified variants in three genes that influence both the efficacy of CAR T-cell therapy and the likelihood of severe side effects. Published today in Science Immunology, these findings represent a first step toward adopting a precision medicine approach in an increasingly used form of cancer immunotherapy.
CAR T-cell therapies have undeniably transformed the treatment of blood cancers, with a rapidly growing number of approvals over the past decade and progressively expanding toward solid tumors. While genetic variants associated with immune-related side effects have been identified for other forms of cancer immunotherapy, such as checkpoint inhibitors, the role of human genetics in CAR T-cell therapy has remained largely unexplored. However, this is particularly important given that most CAR T cells are manufactured from a patient’s own immune cells, meaning the therapy itself carries the patient’s unique genetic makeup.
“Unlike traditional therapeutics that are essentially identical across all patients, CAR T cells are bespoke and harbor all of the ancestral genetic polymorphisms of their parental T cells,” write the study authors, led by Marcela V. Maus, MD, PhD, professor of medicine at Harvard Medical School and director of the Cellular Immunotherapy Program at Massachusetts General Hospital.
Maus and colleagues analyzed data from 236 patients with aggressive lymphoma enrolled across two clinical trials, who had been treated with axicabtagene ciloleucel, a CAR T-cell therapy commercialized by Gilead under the name Yescarta. The analysis combined whole-genome sequencing with detailed biomarker and functional analysis to identify variants affecting the treatment’s efficacy and toxicity.
Among patients who developed treatment-induced toxicity, many carried variants of the STXBP2 gene. Follow-up experiments in human T cells showed that these variants increased the production of inflammatory cytokines and activated macrophages. Consistent with these findings, mutations in the STXBP2 gene have previously been linked to inflammatory bowel disease and a rare immune disease marked by excessive T cell activation.
In contrast, variants in the ADMTSL3 gene were associated with protection against treatment-related toxicity, while variants in the PTPN22 gene were strongly linked to enhanced CAR T-cell expansion—a critical factor that determines treatment efficacy.
“These findings demonstrate that germline genetics shape the safety and activity of engineered immune cell therapies, affecting future design and patient management,” write the scientists. Going forward, they plan to expand this research into larger patient cohorts and a wider range of CAR T-cell therapies to investigate how different genetic variants influence treatment efficacy and the risk of severe side effects across broader clinical settings.
Beyond opening new avenues for precision medicine in CAR T-cell therapy, the researchers noted that these findings could also inform the development of off-the-shelf CAR T-cell therapies where donor-derived T cells are used instead of a patient’s own cells. This approach could enable a more precise selection of donor T cells optimized to maximize therapeutic benefit while minimizing toxicity risks.
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