Inherited genes may shape CAR T-cell outcomes

Clinical takeaway: Germline genetics are not ready to guide routine CAR T-cell treatment decisions, but variants affecting T-cell degranulation and signaling may help explain why some patients develop early toxicity or unusually robust cellular expansion.

Genetic profiling could eventually help clinicians anticipate CAR T-cell toxicity, select donors for allogeneic products, and engineer more effective cellular therapies, although the findings require validation in larger, more diverse cohorts.

Investigators analyzed whole-genome sequences from 236 patients with aggressive lymphoma treated with axicabtagene ciloleucel in the ZUMA-1 and ZUMA-7 trials. Analyses focused on 78 and 115 patients of European ancestry, respectively.

In ZUMA-1, all 6 patients carrying potentially damaging STXBP2 variants developed the study’s combined toxicity endpoint by day 10, compared with 50% of noncarriers. Toxicity appeared earlier among carriers, at a median of 5 versus 7 days. However, this association was not reproduced in ZUMA-7, which included less heavily pretreated patients with lower baseline inflammation.

Laboratory experiments supported a biologic link: STXBP2-deficient or variant-expressing CAR T cells showed impaired degranulation, reduced cytotoxicity, greater interferon-γ production, and enhanced macrophage inflammatory signaling.

Across both trials, ADAMTSL3 variants were enriched among patients with less toxicity and were associated with lower levels of interleukin-15, a cytokine linked to neurologic adverse events. PTPN22 variants, present in about 5% of patients, were associated with the greatest CAR T-cell expansion in both cohorts, although response rates were similar between carriers and noncarriers.

“Each CAR-T cell product is unique to the person from whom it is manufactured,” lead author Mark B. Leick, MD, said, underscoring how inherited variation may influence the behavior of these “living drugs.”

The authors cautioned that the variants were uncommon, the cohorts were predominantly of European ancestry, and applicability to other CAR constructs and malignancies remains uncertain.

Source: Leick MB, et al. (2026 July 24) Sci Immunol. Genomic correlates of clinical CAR T cell activity