Authors
Mark B Leick, Baihe Sun, Filippo Birocchi, Kathleen M E Gallagher, Alexandra Bratt, Seunghun Han, Grace Martin, Harrison J Silva, Rebecca C Larson, Tyler M Chinsky, Hoyin Chu, Christopher R Reilly, Michael C Kann, Bryan D Choi, Sabrina Camp, Riaz Gillani, Merle Phillips, Tamina Kienka, Stefanie R Bailey, Charlotte E Graham, Max Jan, Nicholas S Moore, Nora Horick, Justin Budka, Simone Filosto, Chad M Williams, Ali Hosseini Rad, Rhine R Shen, Eliezer Van Allen, Saud AlDubayan, Marcela V Maus
Published in
Science immunology. Volume 11. Issue 121. Pages eaef4134. Jul 24, 2026. Epub Jul 24, 2026.
Abstract
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.
PMID:
42497245
Bibliographic data and abstract were imported from PubMed on 25 Jul 2026.
Read full publication at:
Please sign in
to see all details.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 5
- Comments 0