{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T16:06:19Z","timestamp":1772553979113,"version":"3.50.1"},"reference-count":50,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"unspecified","delay-in-days":2,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002704","name":"Fundaci\u00f3n Cient\u00edfica Asociaci\u00f3n Espa\u00f1ola Contra el C\u00e1ncer","doi-asserted-by":"publisher","award":["LABAE21971FERN"],"award-info":[{"award-number":["LABAE21971FERN"]}],"id":[{"id":"10.13039\/501100002704","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100023479","name":"CRIS Cancer Foundation","doi-asserted-by":"publisher","award":["PR_TMT_2023-6"],"award-info":[{"award-number":["PR_TMT_2023-6"]}],"id":[{"id":"10.13039\/501100023479","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["ICI19\/00025"],"award-info":[{"award-number":["ICI19\/00025"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI22\/00647"],"award-info":[{"award-number":["PI22\/00647"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002809","name":"Generalitat de Catalunya","doi-asserted-by":"publisher","award":["2021SGR01292"],"award-info":[{"award-number":["2021SGR01292"]}],"id":[{"id":"10.13039\/501100002809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"International Myeloma Society - Paula and Rodger Riney Foundation Translational Research Award","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100005774","name":"Universitat de Barcelona","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100005774","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,2,10]]},"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>B-cell maturation antigen (BCMA) is the main target for chimeric antigen receptor (CAR)-T cells in multiple myeloma (MM), demonstrating promising outcomes. However, unlike what happens with CART19 in lymphoblastic leukemia and non-Hodgkin's lymphoma, a high proportion of patients will relapse after CAR-T BCMA therapy due to insufficient antigen expression, low CAR-T cell persistence and\/or T-cell exhaustion. In other B cell malignancies, second-generation anti-CD19 4-1BB CARs with CD28-transmembrane domain (TMD) have shown high efficacy and a favorable toxicity profile. We have developed a second-generation CD8\u03b1-TM BCMA-4-1BB\u03b6 CAR-T product, ARI0002h (Cesnicabtagene-autoleucel) for patients with relapsed\/refractory MM. We hypothesized that replacing the TMD of ARI0002h with a CD28-TMD could increase efficacy and reduce tumor escape while maintaining a tolerable toxicity profile.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We generated CAR-T cells using T-cells isolated from buffy coats and evaluated the efficacy and fitness of CAR-Ts at day 8\u201310 of expansion against several MM cell lines. In vitro analyses included cytotoxicity, proliferation, cytokine secretion, T-cell subset markers, activation and exhaustion profiling, metabolomic assays, and RNA-seq after multiple tumor challenges. In in vivo xenograft studies using NSG mice, with tumor cells expressing GFP-ffLuc, disease progression was monitored weekly via bioluminescence imaging.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Despite showing similar in vitro performance regarding cytotoxicity, proliferation and cytokine production, ARI2h-TM28 outperforms ARI0002h in a low BCMA expression setting and achieves superior in vivo tumor control and survival in relapse models with antigen downregulation. Furthermore, ARI2h-TM28 showed an optimized metabolic profile, more oxidative and energetic compared with ARI0002h, with downregulation of proinflammatory genes in CD8 T cells, contributing altogether both to reduced exhaustion and increased persistence of the CARs, improving their efficacy in preclinical models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Incorporating a CD28-TMD into the ARI0002h CAR enhances tumor control even in relapse models with downregulation of the target antigen, offering improved long-term disease management. This modification increases potency against MM tumor cell lines with both normal and reduced BCMA expression, demonstrating superior metabolic endurance and in vivo activity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-011864","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T13:15:20Z","timestamp":1772543720000},"page":"e011864","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Enhanced antitumoral activity of the academic CAR-T ARI0002h against normal and low BCMA-expressing myeloma cells after incorporating a transmembrane CD28 domain"],"prefix":"10.1136","volume":"14","author":[{"given":"Oriol","family":"Cardus","sequence":"first","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"},{"name":"Department of Medicine, University of Barcelona, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joan","family":"Ma\u00f1\u00e9 Pujol","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"},{"name":"Department of Medicine, University of Barcelona, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"de Daniel","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"},{"name":"Department of Medicine, University of Barcelona, Barcelona, Spain"},{"name":"Amyloidosis and Multiple Myeloma Unit, Department of Hematology, Hospital Cl\u00ednic of Barcelona, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David F","family":"Moreno","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"},{"name":"Department of Medicine, University of Barcelona, Barcelona, Spain"},{"name":"Amyloidosis and Multiple Myeloma Unit, Department of Hematology, Hospital Cl\u00ednic of Barcelona, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theo Gremen M","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Pr\u00f3-Sangue Hemocentro de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"},{"name":"Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM\/31), Departament of Hematology and Cell Therapy, Hospital das Cl\u00ednicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony M","family":"Battram","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergi V","family":"Salsench","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorena","family":"Perez-Amill","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helena","family":"Llobregat","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judit","family":"Carpio M\u00e1rmol","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"},{"name":"Department of Medicine, University of Barcelona, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0612-2693","authenticated-orcid":false,"given":"Beatriz","family":"Martin-Antonio","sequence":"additional","affiliation":[{"name":"Centro de Terapias Avanzadas, Instituto de Salud Carlos III, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7921-5420","authenticated-orcid":false,"given":"Aina","family":"Oliver-Caldes","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"},{"name":"Department of Medicine, University of Barcelona, Barcelona, Spain"},{"name":"Amyloidosis and Multiple Myeloma Unit, Department of Hematology, Hospital Cl\u00ednic of Barcelona, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Mun\u00e1rriz","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"},{"name":"Department of Medicine, University of Barcelona, Barcelona, Spain"},{"name":"Amyloidosis and Multiple Myeloma Unit, Department of Hematology, Hospital Cl\u00ednic of Barcelona, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3064-1648","authenticated-orcid":false,"given":"Manel","family":"Juan","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"},{"name":"Department of Immunology, Hospital Cl\u00ednic of Barcelona, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alvaro","family":"Urbano-Ispizua","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"},{"name":"Department of Medicine, University of Barcelona, Barcelona, Spain"},{"name":"Amyloidosis and Multiple Myeloma Unit, Department of Hematology, Hospital Cl\u00ednic of Barcelona, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5694-0921","authenticated-orcid":false,"given":"Luis Gerardo","family":"Rodr\u00edguez-Lobato","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"},{"name":"Department of Medicine, University of Barcelona, Barcelona, Spain"},{"name":"Amyloidosis and Multiple Myeloma Unit, Department of Hematology, Hospital Cl\u00ednic of Barcelona, Barcelona, 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