肝动脉灌注联合线粒体分裂抑制剂Mdivi-1处理增强HBVs-CAR-T细胞抗HCC疗效的研究

受肿瘤微环境制约，嵌合抗原受体T细胞（CAR-T）在肝细胞癌（HCC）等实体瘤中疗效欠佳，如何增强CAR-T浸润和杀伤HCC的能力是突破该治疗瓶颈的关键。首先，肝动脉灌注可使CAR-T精准抵达肝脏肿瘤部位，维持局部CAR-T细胞浓度，是克服CAR-T对实体瘤浸润不足的实用策略。其次，我们前期研究构建了靶向乙肝病毒表面抗原的CAR-T（HBVs-CAR-T），证实了过表达CD39能显著增强其杀伤HCC的能力，并筛选到可提升CAR-T CD39表达的化合物Mdivi-1。由此猜想肝动脉灌注联合Mdivi-1处理可增强HBVs-CAR-T清除HCC的效果。鉴此，本项目拟探究Mdivi-1通过提升CD39的表达增强HBVs-CAR-T抗HCC的作用及机制；评估经肝动脉灌注Mdivi-1处理后的HBVs-CAR-T治疗HCC的疗效及安全性；为临床上CAR-T治疗HCC提供新的联合治疗模式和理论依据。

There are still bottlenecks for chimeric antigen receptor-T cell (CAR-T) in the treatment of hepatocellular carcinoma (HCC) owing to the restriction of tumor immunosuppressive microenvironment. Enhancing the infiltration and killing ability of CAR-T cells is the key to break through the bottleneck of CAR-T therapy in HCC. First, hepatic arterial infusion can promote the accurate delivery of CAR-T to the tumor site and the maintenance of its local concentration, which is a practical strategy to overcome the insufficient infiltration of CAR-T in solid tumors. Secondly, in our previous study, we constructed CAR-T targeting HBV surface antigen (HBVs-CAR-T), and confirmed that overexpression of CD39 significantly enhanced its anti-HCC ability. Therefore we screened a compound Mdivi-1 that can specifically up-regulate CAR-T CD39 expression, and speculated that hepatic arterial perfusion combined with Mdivi-1 treatment can enhance the efficacy of CAR-T in anti-solid tumors. Therefore, this project aims to explore the mechanism of mdivi-1 treatment in enhancing the anti-HCC ability of HBVs-CAR-T by up-regulating CD39 expression; to evaluate the efficacy and security of HBVs-CAR-T cells treated with mdivi-1 through hepatic artery in the treatment of HCC. This study provides a new therapeutic model and theoretical basis for the clinical treatment of HCC with CAR T.