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

Sep 30, 2026

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CD19 CAR-T therapy has shown strong responses in relapsed or refractory non-Hodgkin lymphoma, yet failures persist due to CD19 loss or downregulation after treatment. Because CD19 and BCMA are co-expressed in non-Hodgkin lymphoma, dual targeting was investigated to improve durability. Multiple dual-targeting designs were optimized, including co-transduction with two lentiviral vectors, bicistronic, tandem, and loop or pool strategies. Anti-CD19/BCMA ARI0003 CAR-T cells were generated efficiently, showed high-avidity tumor targeting, outperformed CD19-only CAR-T and other dual approaches in vitro and in vivo, maintained activity after CD19 CAR-T in xenografts and relapsed patient-derived models, and were manufacturable under GMP with reduced genotoxicity risk. A first-in-human phase 1 trial (CARTDBG-01; NCT06097455) initiated evaluation of ARI0003 safety and efficacy.

LanguageEnglish

CategoryResearch & Report

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Pages19

Reading Time48 min

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INTRODUCTION

Dual-targeting CAR-T strategies in NHL

CD19 loss, antigen density, and clinical relapse

Original Article ARI0003: Co-transduced CD19/BCMA dual-targeting CAR-T cells for the treatment of non-Hodgkin lymphoma Mireia Bachiller, 1, 11 Nina Barceló-Genestar, 1, 11 Alba Rodriguez-Garcia, 1 Leticia Alserawan,2 Cèlia Dobaño-López, 1,3 Marta Giménez-Alejandre, 1 Joan Castellsagué, 1 Salut Colell, 1 Marc Otero-Mateo, 1 Asier Antoñana-Vildosola, 1 Marta Español-Rego, 1,2 Noelia Ferruz,4 Mariona Pascal, 1,2,5 Beatriz Martín-Antonio, 1,6 Xavier M. Anguela,7 Cristina Fillat, 1,8 Eulàlia Olesti, 1,5,9 Gonzalo Calvo, 1,5,9 Manel Juan, 1,2 Julio Delgado, 1,3,5, 10 Patricia Pérez-Galán, 1,3 Álvaro Urbano-Ispizua, 1,5, 10, 12 and Sonia Guedan 1, 12 1Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi Sunyer (FRCB-IDIBAPS), 08036 Barcelona, Spain; 2Department of Immunology, Hospital Clínic, 08036 Barcelona, Spain; 3Centro de Investigación Biomédica en Red-Oncología (CIBERONC), 28029 Madrid, Spain; 4Centre for Genomic Regulation (CRG), Barcelona Institute for Science and Technology, 08003 Barcelona, Spain; 5University of Barcelona, 08034 Barcelona, Spain; 6Instituto de Salud Carlos III, 28029 Madrid, Spain; 7Estuary Biotherapeutics, Philadelphia, PA 19104, USA; 8Centro de Investigación en Red-Enfermedades Raras (CIBERER), 08036 Barcelona, Spain; 9Department of Clinical Pharmacology, Hospital Clínic, 08036 Barcelona, Spain; 10Department of Hematology, Hospital Clínic, 08036 Barcelona, Spain 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 antiCD19/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 (CARTDBG-01; this study was registered at [ClinicalTrials.gov](ClinicalTrials.gov)[ ](ClinicalTrials.gov)[NCT06097455]) has been initiated to evaluate the safety andefﬁcacy of ARI0003 in NHL. INTRODUCTION Chimeric antigen receptor (CAR) T cell therapy targeting CD19 has demonstrated unprecedented clinical responses in patients with B cell lymphoid malignancies refractory to conventional treatments.1–8 However, around 50% of patients with large B cell lymphoma do not achieve a complete response (CR), and approximately 40%– 50% of patients who achieve a CR subsequently relapse.3,4,9 CD19 loss has been widely described after CD19 CAR-T cell relapse in B cell acute lymphoblastic leukemia (ALL) and in diffuse large B cell lymphoma (DLBCL) .10–13 Additionally, interpatient variability of CD19 expression together with heterogeneity in CD19 expression at the time of diagnosis seems to hold special relevance in DLBCL relapses.14 Diminished expression on CD19 correlates with poor clinical outcomes and reduced event-free survival, suggesting that antigen density below a cert

FAQs

Why develop a dual-targeting CAR-T approach for non-Hodgkin lymphoma?

CD19 CAR-T responses can be limited by refractory disease and relapse linked to CD19 loss or downregulation. Since CD19 and BCMA are co-expressed in NHL, dual targeting was hypothesized to enhance long-term efficacy and reduce antigen escape.

What is ARI0003 and how was it generated?

ARI0003 refers to anti-CD19/BCMA CAR-T cells produced through optimized co-transduction of two lentiviral vectors, designed to minimize competition for cellular resources.

What evidence supports ARI0003’s activity and safety readiness?

ARI0003 effectively targeted NHL cells with high avidity and outperformed CD19 CAR-T and other dual-targeting approaches in vitro and in vivo, including low CD19 antigen density models. It also maintained effectiveness after CD19 CAR-T treatment in xenograft models and patient-derived spheroids, and it was manufactured under GMP with reduced genotoxicity risk compared with other dual approaches. A phase 1 trial (CARTDBG-01; NCT06097455) has been initiated to evaluate safety and efficacy.

Sep 30, 2026

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