{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:07:02Z","timestamp":1789016822836,"version":"build-2803163510"},"reference-count":47,"publisher":"BMJ","issue":"11","license":[{"start":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T00:00:00Z","timestamp":1667347200000},"content-version":"unspecified","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Stiftung f\u00fcr Krebsbek\u00e4mpfung","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100013362","name":"Swiss Cancer Research Foundation","doi-asserted-by":"publisher","award":["KFS-4542-08-2018-R"],"award-info":[{"award-number":["KFS-4542-08-2018-R"]}],"id":[{"id":"10.13039\/501100013362","id-type":"DOI","asserted-by":"publisher"}]},{"name":"H2020 Marie Sk\u0142odowska-Curie Actions Individual Fellowship","award":["H2020-MSCA-IF-2020, No. 101027973"],"award-info":[{"award-number":["H2020-MSCA-IF-2020, No. 101027973"]}]},{"name":"Department of oncology UNIL CHUV, University of Lausanne and Lausanne University Hospital","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100013849","name":"Fondation Dr Henri Dubois-Ferri\u00e8re Dinu Lipatti","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100013849","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2022,9,13]]},"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) on multiple myeloma (MM) produces fast but not long-lasting responses. Reasons for treatment failure are poorly understood. CARs simultaneously targeting two antigens may represent an alternative. Here, we (1) designed and characterized novel A proliferation inducing ligand (APRIL) based dual-antigen targeting CARs, and (2) investigated mechanisms of resistance to CAR T cells with three different BCMA-binding moieties (APRIL, single-chain-variable-fragment, heavy-chain-only).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Three new APRIL-CARs were designed and characterized. Human APRIL-CAR T cells were evaluated for their cytotoxic function in vitro and in vivo, for their polyfunctionality, immune synapse formation, memory, exhaustion phenotype and tonic signaling activity. To investigate resistance mechanisms, we analyzed BCMA levels and cellular localization and quantified CAR T cell\u2013target cell interactions by live microscopy. Impact on pathway activation and tumor cell proliferation was assessed in vitro and in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>APRIL-CAR T cells in a trimeric ligand binding conformation conferred fast but not sustained antitumor responses in vivo in mouse xenograft models. In vitro trimer-BB\u03b6 CAR T cells were more polyfunctional and formed stronger immune synapses than monomer-BB\u03b6 CAR T cells. After CAR T cell\u2013myeloma cell contact, BCMA was rapidly downmodulated on target cells with all evaluated binding moieties. CAR T cells acquired BCMA by trogocytosis, and BCMA on MM cells was rapidly internalized. Since BCMA can be re-expressed during progression and persisting CAR T cells may not protect patients from relapse, we investigated whether non-functional CAR T cells play a role in tumor progression. While CAR T cell\u2013MM cell interactions activated BCMA pathway, we did not find enhanced tumor growth in vitro or in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Antitumor responses with APRIL-CAR T cells were fast but not sustained. Rapid BCMA downmodulation occurred independently of whether an APRIL or antibody-based binding moiety was used. BCMA internalization mostly contributed to this effect, but trogocytosis by CAR T cells was also observed. Our study sheds light on the mechanisms underlying CAR T cell failure in MM when targeting BCMA and can inform the development of improved treatment strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2022-005091","type":"journal-article","created":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T11:08:45Z","timestamp":1667387325000},"page":"e005091","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":43,"title":["Both APRIL and antibody-fragment-based CAR T cells for myeloma induce BCMA downmodulation by trogocytosis and internalization"],"prefix":"10.1136","volume":"10","author":[{"given":"Nicolas","family":"Camviel","sequence":"first","affiliation":[{"name":"Department of Oncology UNIL CHUV, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland"},{"name":"Ludwig Institute for Cancer Research Lausanne Branch, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benita","family":"Wolf","sequence":"additional","affiliation":[{"name":"Department of Oncology UNIL CHUV, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland"},{"name":"Ludwig Institute for Cancer Research Lausanne Branch, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Croce","sequence":"additional","affiliation":[{"name":"Department of Oncology UNIL CHUV, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland"},{"name":"Ludwig Institute for Cancer Research Lausanne Branch, Lausanne, Switzerland"},{"name":"Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Gfeller","sequence":"additional","affiliation":[{"name":"Department of Oncology UNIL CHUV, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland"},{"name":"Ludwig Institute for Cancer Research Lausanne Branch, Lausanne, Switzerland"},{"name":"Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Zoete","sequence":"additional","affiliation":[{"name":"Department of Oncology UNIL CHUV, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland"},{"name":"Ludwig Institute for Cancer Research Lausanne Branch, Lausanne, Switzerland"},{"name":"Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6440-9970","authenticated-orcid":false,"given":"Caroline","family":"Arber","sequence":"additional","affiliation":[{"name":"Department of Oncology UNIL CHUV, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland"},{"name":"Ludwig Institute for Cancer Research Lausanne Branch, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2022,11,2]]},"reference":[{"key":"2025100303265404000_10.11.e005091.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-020-0427-6"},{"key":"2025100303265404000_10.11.e005091.2","doi-asserted-by":"crossref","first-page":"e446","DOI":"10.1016\/S2352-3026(21)00057-0","article-title":"CAR T-cell therapy for multiple myeloma: state of the art and prospects","volume":"8","author":"van de Donk","year":"2021","journal-title":"Lancet Haematol"},{"key":"2025100303265404000_10.11.e005091.3","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-2422"},{"key":"2025100303265404000_10.11.e005091.4","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20031330"},{"key":"2025100303265404000_10.11.e005091.5","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.6.3655"},{"key":"2025100303265404000_10.11.e005091.6","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-06-2043"},{"key":"2025100303265404000_10.11.e005091.7","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-05-781351"},{"key":"2025100303265404000_10.11.e005091.8","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-04-015958"},{"key":"2025100303265404000_10.11.e005091.9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2024850"},{"key":"2025100303265404000_10.11.e005091.10","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1817226"},{"key":"2025100303265404000_10.11.e005091.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01245-5"},{"key":"2025100303265404000_10.11.e005091.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21177-5"},{"key":"2025100303265404000_10.11.e005091.13","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019000703"},{"key":"2025100303265404000_10.11.e005091.14","doi-asserted-by":"crossref","DOI":"10.1182\/blood-2019-126689","article-title":"Phase 1 first-in-human study of AUTO2, the first chimeric antigen receptor (CAR) T cell targeting April for patients with relapsed\/refractory multiple myeloma (RRMM)","volume":"134","author":"Popat","year":"2019","journal-title":"Blood"},{"key":"2025100303265404000_10.11.e005091.15","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-04-711903"},{"key":"2025100303265404000_10.11.e005091.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-14119-9"},{"key":"2025100303265404000_10.11.e005091.17","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20042309"},{"key":"2025100303265404000_10.11.e005091.18","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.661405"},{"key":"2025100303265404000_10.11.e005091.19","unstructured":"Kochenderfer J . National cancer Institute (NCI). T cells expressing a novel Fully-Human Anti-BCMA CAR for treating multiple myeloma, 2018. Available: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03602612"},{"key":"2025100303265404000_10.11.e005091.20","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1054-1"},{"key":"2025100303265404000_10.11.e005091.21","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019000050"},{"key":"2025100303265404000_10.11.e005091.22","doi-asserted-by":"publisher","DOI":"10.1172\/JCI126397"},{"key":"2025100303265404000_10.11.e005091.23","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-03-707547"},{"key":"2025100303265404000_10.11.e005091.24","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2015.68"},{"key":"2025100303265404000_10.11.e005091.25","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0609.2009.01262.x"},{"key":"2025100303265404000_10.11.e005091.26","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2017.6528"},{"key":"2025100303265404000_10.11.e005091.27","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-01-264424"},{"key":"2025100303265404000_10.11.e005091.28","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-01-691162"},{"key":"2025100303265404000_10.11.e005091.29","unstructured":"Autolus Limited . University College London Hospitals NHS Foundation Trust TCNFT, Freeman Hospital, the Newcastle upon Tyne Hospitals NHS Foundation Trust, VU University Medical Centre Amsterdam. APRIL CAR T cells (AUTO2) targeting BCMA and TACI for the treatment of multiple myeloma (APRIL), 2020. Available: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03287804"},{"key":"2025100303265404000_10.11.e005091.30","unstructured":"Frigault M . TriPRIL CAR T cells in multiple myeloma, 2021. Available: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05020444"},{"key":"2025100303265404000_10.11.e005091.31","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2018.77.8084"},{"key":"2025100303265404000_10.11.e005091.32","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.14145"},{"key":"2025100303265404000_10.11.e005091.33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1819745116"},{"key":"2025100303265404000_10.11.e005091.34","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-018-0681-6"},{"key":"2025100303265404000_10.11.e005091.35","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/S0140-6736(21)00933-8","article-title":"Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b\/2 open-label study","volume":"398","author":"Berdeja","year":"2021","journal-title":"Lancet"},{"key":"2025100303265404000_10.11.e005091.36","doi-asserted-by":"publisher","DOI":"10.1158\/2643-3230.BCD-20-0227"},{"key":"2025100303265404000_10.11.e005091.37","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-013-1924-9"},{"key":"2025100303265404000_10.11.e005091.38","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401647"},{"key":"2025100303265404000_10.11.e005091.39","unstructured":"Cowan A , Fred Hutch-University of Washington Cancer Consortium, Juno Therapeutics Inc, Fred Hutchinson Cancer Research Center, The Leukemia and Lymphoma Society . BCMA-specific CAR T-cells combined with a gamma secretase inhibitor (JSMD194) to treat relapsed or persistent multiple myeloma 2018 https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03502577"},{"key":"2025100303265404000_10.11.e005091.40","doi-asserted-by":"publisher","DOI":"10.1158\/2643-3230.BCD-20-0020"},{"key":"2025100303265404000_10.11.e005091.41","doi-asserted-by":"crossref","DOI":"10.3390\/biomedicines9101422","article-title":"Novel CS1 CAR-T cells and bispecific CS1-BCMA CAR-T cells effectively target multiple myeloma","volume":"9","author":"Golubovskaya","year":"2021","journal-title":"Biomedicines"},{"key":"2025100303265404000_10.11.e005091.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16160-5"},{"key":"2025100303265404000_10.11.e005091.43","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2021.1959102"},{"key":"2025100303265404000_10.11.e005091.44","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-021-01170-7"},{"key":"2025100303265404000_10.11.e005091.45","doi-asserted-by":"crossref","first-page":"e521","DOI":"10.1016\/S2352-3026(19)30115-2","article-title":"A combination of humanised anti-CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, phase 2 trial","volume":"6","author":"Yan","year":"2019","journal-title":"Lancet Haematol"},{"key":"2025100303265404000_10.11.e005091.46","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-021-01923-x"},{"key":"2025100303265404000_10.11.e005091.47","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27853-w"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2022-005091","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T10:27:01Z","timestamp":1759487221000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2022-005091"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11]]},"references-count":47,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11,2]]},"published-print":{"date-parts":[[2022,11]]}},"alternative-id":["10.1136\/jitc-2022-005091"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2022-005091","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11]]}}}