{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:58:42Z","timestamp":1790859522261,"version":"4.1.0"},"reference-count":25,"publisher":"BMJ","issue":"9","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"unspecified","delay-in-days":17,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["1K08CA289948-01"],"award-info":[{"award-number":["1K08CA289948-01"]}]},{"name":"NIH","award":["K99CA303346"],"award-info":[{"award-number":["K99CA303346"]}]},{"name":"NIH","award":["R01CA238268"],"award-info":[{"award-number":["R01CA238268"]}]},{"name":"NIH","award":["R01CA249062"],"award-info":[{"award-number":["R01CA249062"]}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["BL 2044\/1-1"],"award-info":[{"award-number":["BL 2044\/1-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014547","name":"Parker Institute for Cancer Immunotherapy","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100014547","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,8,29]]},"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:p>\n                    In relapsed\/refractory multiple myeloma, the approved B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T cell product ciltacabtagene autoleucel (cilta-cel) shows higher response rates than idecabtagene vicleucel (ide-cel) in pivotal trials and real-world comparisons. This advantage has been attributed to the biparatopic dual-VHH (dVHH) binder of cilta-cel. However, the products also differ in the gene regulatory elements driving CAR expression: cilta-cel uses a human elongation factor \u03b1 (EF1\u03b1) promoter in conjunction with a woodchuck hepatitis post-transcriptional regulatory element (EF1\u03b1\n                    <jats:sup>+WPRE<\/jats:sup>\n                    ), whereas ide-cel uses a myeloproliferative sarcoma virus enhancer (MND) promoter without WPRE (MMD\n                    <jats:sup>-WPRE<\/jats:sup>\n                    ). The role of these elements in CAR-T cell efficacy remains unexplored.\n                  <\/jats:p>\n                  <jats:p>\n                    We generated lentiviral vectors where the CAR transgene was composed of either a dVHH-based or a single-chain variable fragment (scFv)-based BCMA-CAR with a 4-1BB costimulatory and a CD3\u03b6 signaling domain, expressed either by EF1\u03b1\n                    <jats:sup>+WPRE<\/jats:sup>\n                    or MND\n                    <jats:sup>-WPRE<\/jats:sup>\n                    . Primary human T cells or a nuclear factor of activated T cells (NFAT)-GFP Jurkat reporter line were compared at matched vector copy numbers (VCN) or CAR surface expression. Antitumor efficacy was assessed in MM.1S-engrafted NSG mice.\n                  <\/jats:p>\n                  <jats:p>\n                    When transduced at the same multiplicities of infection, MND\n                    <jats:sup>-WPRE<\/jats:sup>\n                    CAR-T cells reached higher VCN and transduction rates than EF1\u03b1\n                    <jats:sup>+WPRE<\/jats:sup>\n                    regardless of the binder type. In an NFAT-GFP reporter assay, unstimulated MND\n                    <jats:sup>-WPRE<\/jats:sup>\n                    -driven cells showed higher NFAT and CD69 expression, consistent with greater tonic signaling compared with EF1\u03b1\n                    <jats:sup>+WPRE<\/jats:sup>\n                    . In vivo, independently of the BCMA binder moiety, EF1\u03b1\n                    <jats:sup>+WPRE<\/jats:sup>\n                    -driven CAR-T cells demonstrated superior cytokine secretion and tumor control along with greater survival of mice treated with EF1\u03b1\n                    <jats:sup>+WPRE<\/jats:sup>\n                    compared with MND\n                    <jats:sup>-WPRE<\/jats:sup>\n                    -driven CAR-T cells.\n                  <\/jats:p>\n                  <jats:p>\n                    CAR-T cells expressing the CAR under MND\n                    <jats:sup>-WPRE<\/jats:sup>\n                    showed greater gene transfer during manufacturing, but this did not translate into superior function in vivo. The advantage attributed to cilta-cel\u2019s dual VHH binder was lost when expressed under MND\n                    <jats:sup>-WPRE<\/jats:sup>\n                    and, conversely, ide-cel\u2019s scFv binder achieved better antitumor activity when expressed under EF1\u03b1\n                    <jats:sup>+WPRE<\/jats:sup>\n                    than under MND\n                    <jats:sup>-WPRE<\/jats:sup>\n                    . The efficacy difference between our CAR constructs in xenograft models therefore tracked with the choice of regulatory elements driving CAR expression independently of the binder. It may be better to choose gene regulatory elements based on the CAR-T cell function they confer rather than on expression strength alone.\n                  <\/jats:p>","DOI":"10.1136\/jitc-2026-016839","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T13:20:18Z","timestamp":1789737618000},"page":"e016839","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Gene regulatory elements determine efficacy of BCMA-targeted CAR-T cell products"],"prefix":"10.1136","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1379-0876","authenticated-orcid":false,"given":"Viktoria","family":"Blumenberg","sequence":"first","affiliation":[{"name":"Cellular Immunotherapy Program, Mass General Brigham Cancer Institute, Boston, Massachusetts, USA"},{"name":"Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen B","family":"June","sequence":"additional","affiliation":[{"name":"Cellular Immunotherapy Program, Mass General Brigham Cancer Institute, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5214-233X","authenticated-orcid":false,"given":"Filippo","family":"Birocchi","sequence":"additional","affiliation":[{"name":"Cellular Immunotherapy Program, Mass General Brigham Cancer Institute, Boston, Massachusetts, USA"},{"name":"Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9177-0251","authenticated-orcid":false,"given":"Giulia","family":"Escobar","sequence":"additional","affiliation":[{"name":"Cellular Immunotherapy Program, Mass General Brigham Cancer Institute, Boston, Massachusetts, USA"},{"name":"Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Graham","sequence":"additional","affiliation":[{"name":"Comprehensive Cancer Center, King\u2019s College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6040-0819","authenticated-orcid":false,"given":"Yueyang","family":"Fan","sequence":"additional","affiliation":[{"name":"Cellular Immunotherapy Program, Mass General Brigham Cancer Institute, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merle K","family":"Phillips","sequence":"additional","affiliation":[{"name":"Cellular Immunotherapy Program, Mass General Brigham Cancer Institute, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2701-3114","authenticated-orcid":false,"given":"Sangwoo","family":"Park","sequence":"additional","affiliation":[{"name":"Cellular 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6220-4588","authenticated-orcid":false,"given":"Christopher","family":"Kelly","sequence":"additional","affiliation":[{"name":"Cellular Immunotherapy Program, Mass General Brigham Cancer Institute, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9574-3496","authenticated-orcid":false,"given":"Magdi","family":"Elsallab","sequence":"additional","affiliation":[{"name":"Cellular Immunotherapy Program, Mass General Brigham Cancer Institute, Boston, Massachusetts, USA"},{"name":"Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3439-3239","authenticated-orcid":false,"given":"Trisha R","family":"Berger","sequence":"additional","affiliation":[{"name":"Cellular Immunotherapy Program, Mass General Brigham Cancer Institute, 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