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 STXBP2 (syntaxin binding protein 2) were enriched among patients with toxicity in ZUMA-1, although not confirmed in ZUMA-7. Mechanistically, STXBP2-deficient or variant-expressing T cells triggered increased inflammatory cytokine production and macrophage activation. Conversely, variants in ADAMTSL3, a TGFβ (transforming growth factor-β) signaling regulator, correlated with protection from toxicity across both trials. Furthermore, variants in PTPN22, 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.