Genomic correlates of clinical CAR-T cell activity.

Germline variants influence immune checkpoint inhibitor responses, but their role in engineered immune cell therapies, such as chimeric antigen receptor T cells (CAR T cells), remains unclear. We integrated whole germline sequencing from patients with lymphoma treated with axicabtagene ciloleucel CAR T cell products in the ZUMA-1 and ZUMA-7 clinical trials with detailed biomarker and functional analyses to identify variants influencing clinical toxicity and pharmacokinetics. Putative deleterious variants in () were enriched among patients with toxicity in ZUMA-1, although not confirmed in ZUMA-7. Mechanistically, deficient or variant-expressing T cells triggered increased inflammatory cytokine production and macrophage activation. Conversely, variants in , a TGFβ (transforming growth factor-β) signaling regulator, correlated with protection from toxicity across both trials. Furthermore, variants in , a negative regulator of T cell receptor signaling, strongly associated with enhanced CAR T cell expansion, a key determinant of efficacy. Together, these findings demonstrate that germline genetics shape the safety and activity of engineered immune cell therapies, affecting future design and patient management.