多发性骨髓瘤的现有CAR-T靶标均有不足之处，因此需要探寻新靶标。FcRL5在骨髓瘤细胞表面过度表达，但不表达于重要的正常细胞。我们的预实验结果显示二代FcRL5 CAR-T在体外显著杀伤骨髓瘤细胞但不损伤重要的正常细胞，提示FcRL5可作为潜在的靶标。同时，我们发现骨髓瘤细胞能诱导FcRL5 CAR-T上调免疫抑制分子PD-1。基于这些，我们提出FcRL5 CAR-T联合PD-1/PD-L1信号阻断的新方案。本项目首先评估FcRL5 作为CAR-T靶标的有效性和安全性；进一步明确以共表达sPD-1-Ig的新策略阻断PD-1/PD-L1信号对FcRL5 CAR-T抗骨髓瘤作用的影响，并探寻PD-1/PD-L1信号影响FcRL5 CAR-T效应的分子机制。本项目的实施能明确FcRL5 CAR-T联合sPD1-Ig过表达治疗骨髓瘤的效应及机制，其临床转化将为复发难治性骨髓瘤提供新的治疗策略。

Identification of novel chimeric antigen receptor-expressing T cell (CAR-T) targets for multiple myeloma (MM) is needed considering that the antigen targets available have some limitation. FcRL5 is overexpressed on the surface of myeloma cells but absent in essential normal cells. Our preliminary data showed that second generation of FcRL5-redirected CAR-T cells efficiently lysed MM cells with surface FcRL5 expression but spared essential normal cells in vitro, suggesting that FcRL5 may be a candidate target. In addition, the immune inhibitory molecule PD-1 was found to be upregulated in FcRL5-specific CAR-T cells upon stimulation with MM cells. Based on these preliminary data, we propose a new therapeutic approach for MM by combining FcRL5-specific CAR-T cells with blockade of PD-1 signaling. In this project, we will firstly evaluate the anti-MM efficacy and the safety of FcRL5-specific CAR-T cells，and then investigate the impact on the effect of FcRL5-specific CAR-T cells mediated by blockade of PD-1/PD-L1 signaling through overexpression of soluble PD1-Ig, and also attempt to explore the molecular mechanism responsible for the action of PD-1/PD-L1 signaling on FcRL5-specific CAR-T cells. The outcome of our project will validate the anti-myeloma efficacy of FcRL5-redirected CAR-T cells in combination with sPD-1-Ig overexpression and unravel the mechanism of action; and its clinical translation will provide a novel therapeutic strategy for relapsed and refractory MM.