肝细胞癌免疫治疗的机制与临床试验
Mechanisms and Clinical Trials of Hepatocellular Carcinoma Immunotherapy.
作者信息
Huang Shao-Li, Wang Yu-Ming, Wang Quan-Yue, Feng Guang-Gui, Wu Fu-Qing, Yang Liu-Ming, Zhang Xi-He, Xin Hong-Wu
机构信息
Department of Clinical Laboratory, Lianjiang People's Hospital, Zhanjiang, China.
Doctoral Scientific Research Center, Lianjiang People's Hospital, Zhanjiang, China.
出版信息
Front Genet. 2021 Jul 8;12:691391. doi: 10.3389/fgene.2021.691391. eCollection 2021.
Hepatocellular carcinoma (HCC), one of the most common and lethal tumors worldwide, is usually not diagnosed until the disease is advanced, which results in ineffective intervention and unfavorable prognosis. Small molecule targeted drugs of HCC, such as sorafenib, provided only about 2.8 months of survival benefit, partially due to cancer stem cell resistance. There is an urgent need for the development of new treatment strategies for HCC. Tumor immunotherapies, including immune check point inhibitors, chimeric antigen receptor T cells (CAR-T) and bispecific antibodies (BsAb), have shown significant potential. It is known that the expression level of glypican-3 (GPC3) was significantly increased in HCC compared with normal liver tissues. A bispecific antibody (GPC3-S-Fabs) was reported to recruit NK cells to target GPC3 positive cancer cells. Besides, bispecific T-cell Engagers (BiTE), including GPC3/CD3, an aptamer TLS11a/CD3 and EpCAM/CD3, were recently reported to efficiently eliminate HCC cells. It is known that immune checkpoint proteins programmed death-1 (PD-1) binding by programmed cell death-ligand 1 (PD-L1) activates immune checkpoints of T cells. Anti-PD-1 antibody was reported to suppress HCC progression. Furthermore, GPC3-based HCC immunotherapy has been shown to be a curative approach to prolong the survival time of patients with HCC in clinically trials. Besides, the vascular endothelial growth factor (VEGF) inhibitor may inhibit the migration, invasion and angiogenesis of HCC. Here we review the cutting-edge progresses on mechanisms and clinical trials of HCC immunotherapy, which may have significant implication in our understanding of HCC and its immunotherapy.
肝细胞癌(HCC)是全球最常见且致命的肿瘤之一,通常在疾病进展到晚期才被诊断出来,这导致干预措施无效且预后不佳。HCC的小分子靶向药物,如索拉非尼,仅提供约2.8个月的生存获益,部分原因是癌症干细胞耐药。迫切需要开发新的HCC治疗策略。肿瘤免疫疗法,包括免疫检查点抑制剂、嵌合抗原受体T细胞(CAR-T)和双特异性抗体(BsAb),已显示出巨大潜力。已知与正常肝组织相比,HCC中磷脂酰肌醇蛋白聚糖-3(GPC3)的表达水平显著升高。据报道,一种双特异性抗体(GPC3-S-Fabs)可募集自然杀伤(NK)细胞靶向GPC3阳性癌细胞。此外,最近有报道称,包括GPC3/CD3、适体TLS11a/CD3和上皮细胞黏附分子(EpCAM)/CD3在内的双特异性T细胞衔接器(BiTE)可有效消除HCC细胞。已知程序性死亡配体1(PD-L1)与程序性死亡-1(PD-1)结合会激活T细胞的免疫检查点。据报道,抗PD-1抗体可抑制HCC进展。此外,基于GPC3的HCC免疫疗法在临床试验中已被证明是一种可延长HCC患者生存时间的治愈性方法。此外,血管内皮生长因子(VEGF)抑制剂可能会抑制HCC的迁移、侵袭和血管生成。在此,我们综述了HCC免疫疗法机制和临床试验的前沿进展,这可能对我们理解HCC及其免疫疗法具有重要意义。