Mireia Bachiller, Nina Barceló-Genestar, Alba Rodriguez-Garcia, Leticia Alserawan, Cèlia Dobaño-López, Marta Giménez-Alejandre, Joan Castellsagué, Salut Colell, Marc Otero-Mateo, Asier Antoñana-Vildosola, Marta Español-Rego, Noelia Ferruz, Mariona Pascal, Beatriz Martín-Antonio, Xavier M Anguela, Cristina Fillat, Eulàlia Olesti, Gonzalo Calvo, Manel Juan, Julio Delgado, Patricia Pérez-Galán, Álvaro Urbano-Ispizua, Sonia Guedan
{"title":"ARI0003:共同转导的 CD19/BCMA 双靶向 CAR-T 细胞用于治疗非霍奇金淋巴瘤。","authors":"Mireia Bachiller, Nina Barceló-Genestar, Alba Rodriguez-Garcia, Leticia Alserawan, Cèlia Dobaño-López, Marta Giménez-Alejandre, Joan Castellsagué, Salut Colell, Marc Otero-Mateo, Asier Antoñana-Vildosola, Marta Español-Rego, Noelia Ferruz, Mariona Pascal, Beatriz Martín-Antonio, Xavier M Anguela, Cristina Fillat, Eulàlia Olesti, Gonzalo Calvo, Manel Juan, Julio Delgado, Patricia Pérez-Galán, Álvaro Urbano-Ispizua, Sonia Guedan","doi":"10.1016/j.ymthe.2024.11.028","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1000,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"ARI0003: Co-transduced CD19/BCMA dual-targeting CAR-T cells for the treatment of non-Hodgkin lymphoma.\",\"authors\":\"Mireia Bachiller, Nina Barceló-Genestar, Alba Rodriguez-Garcia, Leticia Alserawan, Cèlia Dobaño-López, Marta Giménez-Alejandre, Joan Castellsagué, Salut Colell, Marc Otero-Mateo, Asier Antoñana-Vildosola, Marta Español-Rego, Noelia Ferruz, Mariona Pascal, Beatriz Martín-Antonio, Xavier M Anguela, Cristina Fillat, Eulàlia Olesti, Gonzalo Calvo, Manel Juan, Julio Delgado, Patricia Pérez-Galán, Álvaro Urbano-Ispizua, Sonia Guedan\",\"doi\":\"10.1016/j.ymthe.2024.11.028\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>CD19 CAR-T therapy has achieved remarkable responses in relapsed/refractory non-Hodgkin lymphoma (NHL). 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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. 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ARI0003: Co-transduced CD19/BCMA dual-targeting CAR-T cells for the treatment of non-Hodgkin lymphoma.
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.
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.