{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T18:04:08Z","timestamp":1784916248418,"version":"3.55.0"},"reference-count":109,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"121","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Immunol."],"published-print":{"date-parts":[[2026,7,24]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic toggle=\"yes\">STXBP2<\/jats:italic>\n                    (\n                    <jats:italic toggle=\"yes\">syntaxin binding protein 2<\/jats:italic>\n                    ) were enriched among patients with toxicity in ZUMA-1, although not confirmed in ZUMA-7. Mechanistically,\n                    <jats:italic toggle=\"yes\">STXBP2-<\/jats:italic>\n                    deficient or variant-expressing T cells triggered increased inflammatory cytokine production and macrophage activation. Conversely, variants in\n                    <jats:italic toggle=\"yes\">ADAMTSL3<\/jats:italic>\n                    , a TGF\u03b2 (transforming growth factor\u2013\u03b2) signaling regulator, correlated with protection from toxicity across both trials. Furthermore, variants in\n                    <jats:italic toggle=\"yes\">PTPN22<\/jats:italic>\n                    , 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.\n                  <\/jats:p>","DOI":"10.1126\/sciimmunol.aef4134","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T17:58:17Z","timestamp":1784915897000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Genomic correlates of clinical CAR T cell activity"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3111-0221","authenticated-orcid":true,"given":"Mark B.","family":"Leick","sequence":"first","affiliation":[{"name":"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA."},{"name":"Harvard Medical School, Boston, MA 02115, USA."},{"name":"Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA."},{"name":"Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6632-7786","authenticated-orcid":true,"given":"Baihe","family":"Sun","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA."},{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5214-233X","authenticated-orcid":true,"given":"Filippo","family":"Birocchi","sequence":"additional","affiliation":[{"name":"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA."},{"name":"Harvard Medical School, Boston, MA 02115, USA."},{"name":"Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4818-2082","authenticated-orcid":true,"given":"Kathleen M. 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