Cell and Gene Therapy · us
Same CAR-T, Different Responses: Genetic Variants Affect Toxicity and Cell Expansion
Whole-genome data from more than 200 patients with aggressive lymphoma suggest that inherited genetic differences may contribute to CAR-T–related inflammatory toxicity and in vivo expansion; however, some signals were not replicated across trials, and clinical screening remains some way off.
CAR-T therapy uses a patient’s own T cells and modifies them, resulting in a product that varies from person to person. Research now suggests that these differences may arise not only from the manufacturing process, tumor status, and prior treatments, but also from genetic variants present from birth. The findings offer new biological clues as to why some people experience severe side effects while others achieve better cell expansion in the body.
The research team integrated data from two large lymphoma trials, ZUMA-1 and ZUMA-7, analyzing germline whole-genome sequences from more than 200 patients treated with axicabtagene ciloleucel and linking them to clinical toxicity, pharmacokinetics, and biomarkers. Institutions involved in the research included Mass General Brigham, the Broad Institute, and Dana-Farber Cancer Institute. The findings were published in *Science Immunology*.
The finding requiring the most cautious interpretation concerns STXBP2. In ZUMA-1, STXBP2 variants predicted to be damaging were more common among patients who developed toxicity. Experiments also showed that T cells lacking STXBP2 or expressing related variants increased inflammatory cytokines and promoted macrophage activation, providing a potential mechanism for the clinical association. However, this genetic association was not confirmed in ZUMA-7, so STXBP2 cannot yet be considered a reliable risk-prediction tool.
Two other signals were more consistent: ADAMTSL3 variants were associated with lower treatment toxicity in both trials, while PTPN22 variants were strongly associated with greater in vivo expansion of CAR-T cells. Because the degree of expansion is a key indicator affecting CAR-T activity, PTPN22 may reveal a pathway for enhancing cell function. However, the study demonstrated an association with expansion, which cannot be directly equated with improved patient survival or tumor control.
### Background
CAR-T development often focuses first on dose-limiting toxicity, cytokine release syndrome, and neurotoxicity, before asking whether the antitumor response is durable. This study moves the question further upstream: patients receiving the same therapy may have different interactions between immune cells and macrophages because of differences in their germline genetic backgrounds. If subsequent studies can replicate the findings in more populations and across different CAR-T products, the information could potentially be used for risk stratification, help select donors for allogeneic CAR-T, or guide the design of next-generation cell engineering.
At this stage, the evidence remains exploratory. The samples came from two axicabtagene ciloleucel lymphoma trials, the study was limited in size, and at least one important association was not validated across trials. Whether the findings apply to different cancer types, populations, and CAR structures remains to be answered by prospective studies. The research was funded by Kite Pharma; three authors are Kite employees, and patent and financial interests were also disclosed, making future independent validation particularly important.