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) 中表现出令人印象深刻的临床反应。然而，一些 BCMA 缺陷肿瘤患者无法从这种疗法中受益，而其他患者可能会经历 BCMA 抗原丢失导致复发，因此需要识别额外的 CAR-T 靶点。在这里，我们证明 FcRH5 在多发性骨髓瘤细胞上表达，并且可以被 CAR-T 细胞靶向。FcRH5 CAR-T 细胞引发抗原特异性激活、细胞因子分泌和针对 MM 细胞的细胞毒性。此外，FcRH5 CAR-T 细胞在小鼠异种移植模型（包括一种 BCMA 表达缺陷的模型）中表现出强大的杀肿瘤功效。我们还表明，不同形式的可溶性 FcRH5 可以干扰 FcRH5 CAR-T 细胞的功效。最后，与体内单特异性 CAR-T 细胞相比，FcRH5/BCMA 双特异性 CAR-T 细胞可有效识别表达 FcRH5 和/或 BCMA 的 MM 细胞，并表现出更高的功效。这些发现表明，用 CAR-T 细胞靶向 FcRH5 可能代表了一种有前景的 MM 治疗途径。