Liu Zixu, Zhao Linxuan, Liu Hao, Dong Nan, Zhou Ning, Zhang Yu, Yin Tian, He Haibing, Gou Jingxin, Tang Xing, Yang Li, Gao Song
Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang 110116, China.
Department of Pharmaceutics, College of Pharmacy Sciences, Jilin University, Changchun 130021, China.
Int J Pharm. 2022 Nov 25;628:122361. doi: 10.1016/j.ijpharm.2022.122361. Epub 2022 Nov 2.
PD-1/L1 checkpoint blockade has gained approval in terms of treating patients suffering from hepatocellular carcinoma (HCC). It should be noted that the PD-1/L1 inhibitor (α-PD-1/L1) has a low overall response rate when used as a single agent. Accordingly, the combination of α-PD-1/L1 and a series of therapies to further increase the response rate has become a major research direction. In our previous study, we developed a novel norcantharidin (NCTD) liposome emulsion hybrid delivery system (NE) with enhanced anticancer activity and reduced toxicity. In this study, NE was combined with α-PD-1/L1 for treating HCC. The combination therapy exhibited an enhanced antitumor activity, which led to the up-regulated expression levels of white blood cells, interleukin 12 (IL-12), interferon γ (IFN-γ), PD-L1, as well as CD8. Furthermore, the combination of NE and α-PD-1 achieved the optimal efficiency. NCTD-based chemotherapy is capable of synergizing with α-PD-1/L1 while enhancing checkpoint immunotherapy. It follows a mechanism that NCTD agonizes the non-canonical NF-κB pathway of dendritic cells for better activating CD8T cells. Furthermore, NCTD may enhance antitumor immunity due to the leukogenic effect. In brief, new therapeutic regimens were provided for anti-HCC treatment by integrating NE to PD-1/L1 immunotherapy.
程序性死亡蛋白1（PD-1）/程序性死亡配体1（PD-L1）检查点阻断疗法已获批用于治疗肝细胞癌（HCC）患者。需要注意的是，PD-1/PD-L1抑制剂（α-PD-1/L1）单药使用时总体缓解率较低。因此，将α-PD-1/L1与一系列疗法联合以进一步提高缓解率已成为主要研究方向。在我们之前的研究中，我们开发了一种具有增强抗癌活性和降低毒性的新型去甲斑蝥素（NCTD）脂质体乳液混合递送系统（NE）。在本研究中，将NE与α-PD-1/L1联合用于治疗HCC。联合疗法表现出增强的抗肿瘤活性，导致白细胞、白细胞介素12（IL-12）、干扰素γ（IFN-γ）、PD-L1以及CD8的表达水平上调。此外，NE与α-PD-1联合取得了最佳疗效。基于NCTD的化疗能够与α-PD-1/L1协同作用，同时增强检查点免疫疗法。其机制是NCTD作用于树突状细胞的非经典核因子κB（NF-κB）途径以更好地激活CD8 + T细胞。此外，由于生白作用，NCTD可能增强抗肿瘤免疫力。简而言之，通过将NE整合到PD-1/L1免疫疗法中，为抗HCC治疗提供了新的治疗方案。
