双免治疗及抗体药物偶联物在晚期胃癌治疗中应用进展  

Application progress of dual immunotherapy and antibody drug conjugates in the treatment of advanced gastric cancer

作　　者：王静远 刘天舒 WANG Jing-yuan;LIU Tian-shu(Department of Medical Oncology,Cancer Center,Zhongshan Hospital,Fudan University,Shanghai 200032,China)

机构地区：[1]复旦大学附属中山医院肿瘤内科肿瘤防治中心,上海200032

出　　处：《中国实用外科杂志》2024年第10期1179-1185,共7页Chinese Journal of Practical Surgery

基　　金：国家自然科学基金青年项目(No.82202892)。

摘　　要：由于存在免疫逃逸,免疫检查点抑制剂(ICIs)单药治疗生存获益有限,促使组合疗法的出现。双重阻断免疫疗法在抗肿瘤作用机制上存在互补,但同时也增加了治疗相关不良反应的发生风险。双特异性抗体(bsAbs)在一定程度上实现了疗效与安全性的平衡。但双重ICIs组合疗法和bsAbs均有其局限性。双重ICIs组合疗法中的固定药物配对以及bsAbs中的固定抗体价态对其剂量、疗效和适应证施加了诸多限制。免疫相关不良反应和医疗成本的增加,以及治疗方案的选择,仍是需要长期探索的领域。另一方面,抗体药物偶联物(ADC)的出现给胃癌靶向治疗带来了革命性的变化。除高特异性的靶标结合特点,ADC类药物特有的“旁观者效应”使其在靶点低表达类人群中依然有效,扩大其应用人群范围。然而,抗原水平下调、缺失、突变导致ADC无法结合到靶点,内化通路产生缺陷或细胞膜上与运输相关的蛋白减少、溶酶体的蛋白水解和酸化功能损坏导致ADC无法分解,或者溶酶体膜表面的运输蛋白变少导致效应分子无法被运送到细胞质,可能影响ADC类药物的抗肿瘤疗效。如何实现ADC类药物耐药逆转依然是今后研究方向之一。Immune evasion is a multi-factorial and multistage process,thus the efficacy of immune checkpoint inhibitors(ICIs)monotherapy is limited,promoting the emergence of combination therapies as a novel vital approach to enhance antitumor efficacy and improve survival results.Dual immune blockade therapies offer complementary mechanisms of antitumor action,but they also increase the risk of treatment-related adverse events.The introduction of bispecific antibodies(BsAbs)addresses this challenge to some extent,achieving a balance between efficacy and safety.However,both dual ICIs combination therapies and BsAbs have their limitations.Fixed drug pairings in dual ICI combinations and fixed antibody valency in bsAbs impose various restrictions on dosage,efficacy,and indications.Immunotherapy-related adverse effects,increased medical costs,and treatment regimen choices,remain areas requiring long-term exploration.Besides,the advent of antibody-drug conjugates(ADCs)has brought a revolutionary change to targeted therapy for gastric cancer.Beyond their highly specific target-binding properties,ADCs exhibit a unique“bystander effect”,allowing them to remain effective in populations with low target expression,thereby broadening their range of application.However,factors such as antigen downregulation,loss,or mutation can prevent ADCs from binding to their targets,defects in internalization pathways or reduced expression of membrane transport proteins,the inability to disintegration of ADCs due to lysosomal proteolytic or acidification dysfunction,or decreased lysosomal membrane transport proteins may hinder the delivery of effector molecules to the cytoplasm,ultimately affecting the antitumor efficacy of ADCs.Reversing ADCs resistance remains a key area of future research.

关 键 词：胃癌 双免治疗 抗体药物偶联物 联合治疗 

分 类 号：R6[医药卫生—外科学]