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Stock, S.* ; Fertig, L.* ; Gottschlich, A.* ; Dörr, J.* ; Märkl, F.* ; Majed, L.* ; Menkhoff, V.D.* ; Grünmeier, R.* ; Rejeski, K.* ; Cordas Dos Santos, D.M.* ; Theurich, S.* ; von Bergwelt-Baildon, M.* ; Endres, S. ; Subklewe, M.* ; Kobold, S.

Comparative performance of scFv-based anti-BCMA CAR formats for improved T cell therapy in multiple myeloma.

Cancer Immunol. Immunother. 73:100 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
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In multiple myeloma (MM), B cell maturation antigen (BCMA)-directed CAR T cells have emerged as a novel therapy with potential for long-term disease control. 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 short linker anti-BCMA CAR demonstrated higher cytokine production, whereas in vitro cytotoxicity, T cell differentiation upon activation and proliferation were superior for the CD28TM.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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Adoptive T Cell Therapy ; Bcma ; Chimeric Antigen Receptor ; Immunotherapy ; Multiple Myeloma ; T Cell Engineering; Chimeric Receptors; Domain; Costimulation; Activation; Expression; Efficacy; Cd137
ISSN (print) / ISBN 0340-7004
e-ISSN 1432-0851
Journal Cancer Immunology, Immunotherapy
Quellenangaben Volume: 73, Issue: 6, Pages: , Article Number: 100 Supplement: ,
Publisher Springer
Publishing Place One New York Plaza, Suite 4600, New York, Ny, United States
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Unit for Clinical Pharmacology (KKG-EKLiP)