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oai:repisalud.isciii.es:20.500.12105/260522025-12-18T12:57:03Zcom_20.500.12105_15322com_20.500.12105_2051com_20.500.12105_2052col_20.500.12105_16961col_20.500.12105_19627

00925njm 22002777a 4500 dc Bachiller, Mireia author Barceló-Genestar, Nina author Rodriguez-Garcia, Alba author Alserawan, Leticia author Dobaño-López, Cèlia author Giménez-Alejandre, Marta author Castellsagué, Joan author Colell, Salut author Otero-Mateo, Marc author Antoñana-Vildosola, Asier author Español-Rego, Marta author Ferruz, Noelia author Pascal, Mariona author Martín-Antonio, Beatriz author Anguela, Xavier M author Fillat, Cristina author Olesti, Eulàlia author Calvo, Gonzalo author Juan, Manel author Delgado, Julio author Pérez-Galán, Patricia author Urbano-Ispizua, Álvaro author Guedan, Sonia author 2025-01-08 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. Bachiller M, Barceló-Genestar N, Rodriguez-Garcia A, Alserawan L, Dobaño-López C, Giménez-Alejandre M, Castellsagué J, Colell S, Otero-Mateo M, Antoñana-Vildosola A, Español-Rego M, Ferruz N, Pascal M, Martín-Antonio B, Anguela XM, Fillat C, Olesti E, Calvo G, Juan M, Delgado J, Pérez-Galán P, Urbano-Ispizua Á, Guedan S. ARI0003: Co-transduced CD19/BCMA dual-targeting CAR-T cells for the treatment of non-Hodgkin lymphoma. Mol Ther. 2025 Jan 8;33(1):317-335. 10.1016/j.ymthe.2024.11.028 1525-0024 1525-0016 Molecular therapy : the journal of the American Society of Gene Therapy 39563035 https://hdl.handle.net/20.500.12105/26052 CAR-T cells Co-transduction Dual targeting Lymphoma ARI0003: Co-transduced CD19/BCMA dual-targeting CAR-T cells for the treatment of non-Hodgkin lymphoma.