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Anti-BCMA CAR T cells with a CD8-based transmembrane (TM) and CD137 (41BB) as intracellular costimulatory domain are in routine clinical use. As the CAR construct architecture can differentially impact performance and efficacy, the optimal construction of a BCMA-targeting CAR remains to be elucidated. Here, we hypothesized that varying the constituents of the CAR structure known to impact performance could shed light on how to improve established anti-BCMA CAR constructs. CD8TM.41BBIC-based anti-BCMA CAR vectors with either a long linker or a short linker between the light and heavy scFv chain, CD28TM.41BBIC-based and CD28TM.CD28IC-based anti-BCMA CAR vector systems were used in primary human T cells. MM cell lines were used as target cells. The\u00a0short linker anti-BCMA CAR demonstrated higher cytokine production, whereas in vitro cytotoxicity, T cell differentiation upon activation and proliferation were superior for the\u00a0CD28TM.CD28IC-based CAR. While CD28TM.CD28IC-based CAR T cells killed MM cells faster, the persistence of 41BBIC-based constructs was superior in vivo. While CD28 and 41BB costimulation come with different in vitro and in vivo advantages, this did not translate into a superior outcome for either tested model. In conclusion, this study showcases the need to study the influence of different CAR architectures based on an identical scFv individually. It indicates that current scFv-based anti-BCMA CAR with clinical utility may already be at their functional optimum regarding the known structural variations of the scFv linker.<\/jats:p>","DOI":"10.1007\/s00262-024-03688-4","type":"journal-article","created":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T13:02:03Z","timestamp":1713358923000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Comparative performance of scFv-based anti-BCMA CAR formats for improved T cell therapy in multiple myeloma"],"prefix":"10.1007","volume":"73","author":[{"given":"Sophia","family":"Stock","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luisa","family":"Fertig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrian","family":"Gottschlich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janina","family":"D\u00f6rr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florian","family":"M\u00e4rkl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lina","family":"Majed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivien D.","family":"Menkhoff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruth","family":"Gr\u00fcnmeier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai","family":"Rejeski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David M.","family":"Cordas dos Santos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastian","family":"Theurich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"von Bergwelt-Baildon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Endres","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marion","family":"Subklewe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastian","family":"Kobold","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,4,17]]},"reference":[{"key":"3688_CR1","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/leu.2017.329","volume":"32","author":"CS Chim","year":"2018","unstructured":"Chim CS, Kumar SK, Orlowski RZ et al (2018) Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond. 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KR received research funding Kite\/Gilead, honoraria from BMS\/Celgene and Novartis and travel support from Kite\/Gilead and Pierre-Fabre. KR serves as a consultant for BMS\/Celgene. ST received honoraria from AMGEN, BMS\/Celgene, GSK, Janssen, Pfizer, Sanofi, and Takeda. MS received industry research support from Amgen, Bristol-Myers Squibb\/Celgene, Gilead, Janssen, Miltenyi Biotec, Morphosys, Novartis, Roche, Seattle Genetics, and Takeda, and serves as a consultant\/advisor to AvenCell, CDR-Life, Ichnos Sciences, Incyte Biosciences, Janssen, Molecular Partners, and Takeda. She serves on the speakers\u2019 bureau at Amgen, AstraZeneca, BMS\/Celgene, Gilead, GSK, Janssen, Novartis, Pfizer, Roche, and Takeda. SK has received honoraria from TCR2 Inc., Novartis, Galapagos, Cymab, Miltenyi, BMS, and GSK. SK and SE are inventors of several patents in the field of immuno-oncology. SK and SE received license fees from TCR2 Inc. and Carina Biotech. SK and SE received research support from TCR2 Inc., Tabby Therapeutics, Plectonic GmbH, Catalym GmbH, and Arcus Bioscience for work unrelated to the manuscript.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Approval was obtained from the ethics committee of LMU Munich. The procedures used in this study adhere to the tenets of the Declaration of Helsinki. All animal experimental studies were approved and performed in accordance with guidelines and regulations implemented by the <i>Regierung von Oberbayern<\/i> (ROB).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"The manuscript does not contain any individual person\u2019s data in any form. No patient consent is necessary for publication.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}}],"article-number":"100"}}