ARI0003: Co-transduced CD19/BCMA dual-targeting CAR-T cells for the treatment of non-Hodgkin lymphoma

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• dc.contributor.author Bachiller, Mireia
• dc.contributor.author Ferruz Capapey, Noelia, 1988-
• dc.contributor.author Guedan, Sonia
• dc.date.accessioned 2025-02-07T08:08:11Z
• dc.date.available 2025-02-07T08:08:11Z
• dc.date.issued 2025
• dc.description.abstract CD19 CAR-T therapy has achieved remarkable responses in relapsed/refractory non-Hodgkin lymphoma (NHL). However, challenges persist, with refractory responses or relapses after CAR-T administration linked to CD19 loss or downregulation. Given the co-expression of CD19 and BCMA in NHL, we hypothesized that dual targeting could enhance long-term efficacy. We optimized different dual-targeting approaches, including co-transduction of two lentiviral vectors, bicistronic, tandem, and loop and pool strategies, based on our academic anti-CD19 (ARI0001) and anti-BCMA (ARI0002h) CAR-T cells. Comparison with anti-CD19/CD20 or anti-CD19/CD22 dual targeting was also performed. We demonstrate that anti-CD19/BCMA CAR-T cells can be effectively generated through the co-transduction of two lentiviral vectors after optimization to minimize competition for cellular resources. Co-transduced T cells, called ARI0003, effectively targeted NHL tumor cells with high avidity, outperforming anti-CD19 CAR-T cells and other dual-targeting approaches both in vitro and in vivo, particularly in low CD19 antigen density models. ARI0003 maintained effectiveness post-CD19 CAR-T treatment in xenograft models and in spheroids from relapsed CART-treated patients. ARI0003 CAR-T cells were effectively manufactured under Good Manufacturing Practice conditions, with a reduced risk of genotoxicity compared to other dual-targeting approaches. A first-in-human phase 1 clinical trial (CARTD-BG-01; this study was registered at ClinicalTrials.gov [NCT06097455]) has been initiated to evaluate the safety and efficacy of ARI0003 in NHL.
• dc.description.sponsorship This study was supported by research funding from “'la Caixa” Foundation to M.J. (LCF/PR/SP23/52950004); the Spanish Ministry of Science and Innovation under a Ramon y Cajal grant RYC2018-024442-I to S.G. and PID2020-119692RB-C22 to C.F.; the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 116026 to S.G. (this joint undertaking receives support from the European Union’s Horizon 2020 research and innovation program and European Federation of Pharmaceutical Industries and Associations), the Spanish Association Against Cancer (INVES222988RODR to A.R.-G.), and the AGAUR_INVESTIGO22 100028TC1 grant, within the framework of the Recovery, Transformation, and Resilience Plan, funded by the European Union’s NextGenerationEU Recovery Mechanism. C.D.-L. was supported by a personal "Formación de personal investigador" fellowship from the Ministry of Economy and competitiveness (PRE2018-083797) associated with the project SAF2017-88275-R to P.P.-G. We also thank the Generalitat de Catalunya for support (AGAUR 2021-SGR-01294) to P.P.-G. M.O.-M. was granted a "Formacion para investigadores en el ámbito de la Investigacin sanitaria" predoctoral training grant (IFI18/00035). B.M.-A. was supported by the Miguel Servet program (grant no. CP21/00111) of the Institute of Health Carlos III. We also acknowledge the support of the CERCA Programme/Generalitat de Catalunya. This work was developed at the Centro Esther Koplowitz, Barcelona, Spain. We thank the Flow Cytometry and Cell Sorting core facility of Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi Sunyer (FRCB-IDIBAPS) for their technical help. We also thank the animal facility of the University of Barcelona.
• dc.format.mimetype application/pdf
• dc.identifier.citation Bachiller M, Barceló-Genestar N, Rodriguez-Garcia A, Alserawan L, Dobaño-López C, Giménez-Alejandre M, et al. ARI0003: Co-transduced CD19/BCMA dual-targeting CAR-T cells for the treatment of non-Hodgkin lymphoma. Mol Ther. 2025 Jan 8;33(1):317-35. DOI: 10.1016/j.ymthe.2024.11.028
• dc.identifier.doi http://dx.doi.org/10.1016/j.ymthe.2024.11.028
• dc.identifier.issn 1525-0016
• dc.identifier.uri http://hdl.handle.net/10230/69521
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof Mol Ther. 2025 Jan 8;33(1):317-35
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RYC2018-024442-I
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-119692RB-C22
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PRE2018-083797
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017-88275-R
• dc.rights © 2024 The Authors. Published by Elsevier Inc. on behalf of The American Society of Gene and Cell Therapy. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.keyword CAR-T cells
• dc.subject.keyword Co-transduction
• dc.subject.keyword Dual targeting
• dc.subject.keyword Lymphoma
• dc.title ARI0003: Co-transduced CD19/BCMA dual-targeting CAR-T cells for the treatment of non-Hodgkin lymphoma
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion