Avidity and functional characterization of CD19/BCMA dual-targeting CAR-T cell designs in NHL

CD19-directed CAR-T therapy has achieved remarkable clinical outcomes in patients with relapsed or refractory non-Hodgkin lymphoma (NHL). Nevertheless, a significant proportion of patients develop primary resistance or relapse, often associated with CD19 antigen loss or downregulation. Given the co-expression of CD19 and BCMA in NHL, we hypothesized that dual antigen targeting could improve therapeutic durability and mitigate antigen escape. To address this, we developed a panel of CD19/BCMA dual-targeting CAR-T cells building on our academic platforms targeting CD19 (varnimcabtagene autoleucel, ARI0001) and BCMA (cesnicabtagene autoleucel, ARI0002h). Multiple strategies were explored, including pooled mono-targeted products, co-transduction with two lentiviral vectors, bicistronic constructs, and tandem/loop CAR designs incorporating dual binding domains within a single receptor. Functional activity and avidity were assessed across varying antigen expression conditions. We found that dual CAR-T cells generated through co-transduction consistently showed superior performance relative to single-target CD19 CAR-T cells and other dual-targeting formats, particularly in models with low CD19 expression. A first-in-human phase I clinical trial (CARTDBG-01; NCT06097455) is currently underway to evaluate the safety and efficacy of ARI0003 in NHL.

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Related publication: Bachiller, M., Barceló-Genestar, N., Rodriguez-Garcia, A., Alserawan, L., Dobaño-López, C., Giménez-Alejandre, M., ... & Guedan, S. (2025). ARI0003: Co-transduced CD19/BCMA dual-targeting CAR-T cells for the treatment of non-Hodgkin lymphoma. Molecular Therapy, 33(1), 317-335. https://doi.org/10.1016/j.ymthe.2024.11.028

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