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.

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Publication Details

Journal
Molecular Therapy
Published
2024-11-19
DOI
https://doi.org/10.1016/j.ymthe.2024.11.028
Citations
23
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
6.50

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article

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

Eulàlia Olesti, Noelia Ferruz, Xavier M. Anguela, Álvaro Urbano-Ispizúa et al.
23 citations
Molecular Therapy
CAR-T cell therapy research
6.50
article

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

Eulàlia Olesti, Noelia Ferruz, Xavier M. Anguela, Álvaro Urbano-Ispizúa, Asier Antoñana-Vildosola, Julio Delgado, Mariona Pascal, Gonzalo Calvo, Marta Español‐Rego, Marta Giménez-Alejandre, Marc Otero-Mateo, Joan Castellsagué, Manel Juan, Sònia Guedan, Cristina Fillat, Letícia Alserawan, Beatriz Martín-Antonio, Patricia Pérez‐Galán, Mireia Bachiller, Alba Rodríguez-García, Salut Colell, Cèlia Dobaño-López, Nina Barceló-Genestar
article en
23 citations

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.

Molecular TherapyVol. 33(1)
Centro de Investigación Biomédica en Red (ES), Hospital Clínic de Barcelona (ES), Barcelona Institute of Science and Technology (ES), Centre for Genomic Regulation (ES), Atara Biotherapeutics (United States) (US), Fundació Clínic per a la Recerca Biomèdica (ES), Centro de Investigación Biomédica en Red de Cáncer (ES)
“la Caixa” Foundation, European Federation of Pharmaceutical Industries and Associations, Ministerio de Ciencia, Innovación y Universidades, Centres de Recerca de Catalunya, European Commission, Fundación Científica Asociación Española Contra el Cáncer, Generalitat de Catalunya, Ministerio de Economía y Competitividad, Ministerio de Ciencia e Innovación, Universitat de Barcelona, Horizon 2020 Framework Programme, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III
Good health and well-being
Openalex Percentile: Top 2%
CAR-T cell therapy research
6.50
DOIOpen Access PDFOpenAlex
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