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.

中文翻译：

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ARI0003：共转导的 CD19/BCMA 双靶向 CAR-T 细胞治疗非霍奇金淋巴瘤


CD19 CAR-T 疗法在复发/难治性非霍奇金淋巴瘤 （NHL） 中取得了显着反应。然而，挑战仍然存在，CAR-T 给药后难治性反应或复发与 CD19 丢失或下调有关。鉴于 CD19 和 BCMA 在 NHL 中的共表达，我们假设双重靶向可以提高长期疗效。我们基于我们的学术抗 CD19 （ARI0001） 和抗 BCMA （ARI0002h） CAR-T 细胞优化了不同的双靶向方法，包括两种慢病毒载体、双顺反子、串联以及环和池策略的共转导。还进行了与抗 CD19/CD20 或抗 CD19/CD22 双重靶向的比较。我们证明，优化后可以通过两种慢病毒载体的共转导有效地产生抗 CD19/BCMA CAR-T 细胞，以最大限度地减少对细胞资源的竞争。共转导的 T 细胞（称为 ARI0003）有效地靶向具有高亲和力的 NHL 肿瘤细胞，在体外和 体内均优于抗 CD19 CAR-T 细胞和其他双靶向方法 ，尤其是在低 CD19 抗原密度模型中。ARI0003 在 CD19 CAR-T 治疗后在异种移植模型和 CART 治疗复发患者的球状体中保持有效性。ARI0003 CAR-T 细胞是在良好生产规范条件下有效制造的，与其他双靶向方法相比，遗传毒性风险降低。一项首次人体 1 期临床试验 （CARTD-BG-01;该研究于 ClinicalTrials.gov 年 [NCT06097455] 注册，以评估 ARI0003 治疗 NHL 的安全性和有效性。