ARI0003: Co-transduced CD19/BCMA Dual-targeting CAR-T Cells for the Treatment of Non-Hodgkin Lymphoma.

in Molecular therapy : the journal of the American Society of Gene Therapy by Mireia Bachiller, Nina Barceló-Genestar, Alba Rodríguez-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

TLDR

  • The study investigates whether combining two targets (CD19 and BCMA) in CAR-T therapy for non-Hodgkin lymphoma (NHL) can improve long-term efficacy compared to targeting only one of the two. The study finds that combining the two targets can effectively target NHL tumor cells with high avidity, outperforming anti-CD19 CAR-T cells and other dual-targeting approaches. The study also finds that the combination of the two targets can maintain effectiveness post-CD19 CAR-T treatment in xenograft models and in spheroids from relapsed CART-treated patients. The study identifies co-transduction of two lentiviral vectors as an effective approach for dual-targeting. The study suggests that ARI0003 CAR-T cells could be a promising approach for the treatment of relapsed/refractory NHL. Future research should focus on further optimization of dual-targeting approaches, evaluation of the efficacy of ARI0003 CAR-T cells in larger patient populations, and exploration of the potential of dual-targeting in other types of cancer.

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, 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 co-transduction of two lentiviral vectors after optimization to minimize competition for cellular resources. Co-transduced T cells, named 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 reduced risk of genotoxicity compared to other dual-targeting approaches. A first-in-human phase I clinical trial (CARTD-BG-01, NCT06097455) has been initiated to evaluate the safety and efficacy of ARI0003 in NHL.

Overview

  • The study aims to investigate the efficacy of dual-targeting CD19 and BCMA in non-Hodgkin lymphoma (NHL) using CAR-T therapy. The hypothesis is that dual-targeting will enhance long-term efficacy compared to anti-CD19 or anti-BCMA CAR-T cells. The study uses different dual-targeting approaches, including co-transduction of two lentiviral vectors, bicistronic, tandem, loop and pool strategies, and compares them with anti-CD19/CD20 or anti-CD19/CD22 dual-targeting. The study demonstrates that anti-CD19/BCMA CAR-T cells can effectively target 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 CAR-T cells 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 reduced risk of genotoxicity compared to other dual-targeting approaches. A first-in-human phase I clinical trial (CARTD-BG-01, NCT06097455) has been initiated to evaluate the safety and efficacy of ARI0003 in NHL.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions detailed in the study. The results show that anti-CD19/BCMA CAR-T cells can effectively target 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 CAR-T cells maintained effectiveness post-CD19 CAR-T treatment in xenograft models and in spheroids from relapsed CART-treated patients. The study demonstrates that dual-targeting CD19 and BCMA can enhance long-term efficacy compared to anti-CD19 or anti-BCMA CAR-T cells.

Implications and Future Directions

  • The study's findings suggest that dual-targeting CD19 and BCMA can enhance long-term efficacy compared to anti-CD19 or anti-BCMA CAR-T cells in non-Hodgkin lymphoma (NHL). The study identifies co-transduction of two lentiviral vectors as an effective approach for dual-targeting. The study also highlights the importance of optimizing dual-targeting approaches to minimize competition for cellular resources. The study suggests that ARI0003 CAR-T cells could be a promising approach for the treatment of relapsed/refractory NHL. Future research should focus on further optimization of dual-targeting approaches, evaluation of the efficacy of ARI0003 CAR-T cells in larger patient populations, and exploration of the potential of dual-targeting in other types of cancer.
Read Full Article