Institute of Blood and Marrow Transplantation, National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, China.
Department of hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Nat Commun. 2023 Jun 20;14(1):3642. doi: 10.1038/s41467-023-39395-4.
BCMA-targeting chimeric antigen receptor (CAR) T cell therapy demonstrates impressive clinical response in multiple myeloma (MM). However, some patients with BCMA-deficient tumours cannot benefit from this therapy, and others can experience BCMA antigen loss leading to relapse, thus necessitating the identification of additional CAR-T targets. Here, we show that FcRH5 is expressed on multiple myeloma cells and can be targeted with CAR-T cells. FcRH5 CAR-T cells elicited antigen-specific activation, cytokine secretion and cytotoxicity against MM cells. Moreover, FcRH5 CAR-T cells exhibited robust tumoricidal efficacy in murine xenograft models, including one deficient in BCMA expression. We also show that different forms of soluble FcRH5 can interfere with the efficacy of FcRH5 CAR-T cells. Lastly, FcRH5/BCMA-bispecific CAR-T cells efficiently recognized MM cells expressing FcRH5 and/or BCMA and displayed improved efficacy, compared with mono-specific CAR-T cells in vivo. These findings suggest that targeting FcRH5 with CAR-T cells may represent a promising therapeutic avenue for MM.
BCMA 靶向嵌合抗原受体 (CAR) T 细胞疗法在多发性骨髓瘤 (MM) 中显示出令人印象深刻的临床反应。然而，一些缺乏 BCMA 的肿瘤患者不能从中受益，而另一些患者则会出现 BCMA 抗原丢失导致复发，因此需要确定其他 CAR-T 靶点。在这里，我们表明 FcRH5 在多发性骨髓瘤细胞上表达，并可以用 CAR-T 细胞进行靶向。FcRH5 CAR-T 细胞引起了针对 MM 细胞的特异性激活、细胞因子分泌和细胞毒性。此外，FcRH5 CAR-T 细胞在包括表达 BCMA 的缺失的小鼠异种移植模型中表现出强大的杀瘤功效。我们还表明，不同形式的可溶性 FcRH5 可以干扰 FcRH5 CAR-T 细胞的疗效。最后，FcRH5/BCMA 双特异性 CAR-T 细胞有效地识别表达 FcRH5 和/或 BCMA 的 MM 细胞，并在体内显示出比单特异性 CAR-T 细胞更高的疗效。这些发现表明，用 CAR-T 细胞靶向 FcRH5 可能是 MM 的一种有前途的治疗方法。
