肿瘤细胞治疗研究
英文原题：Antibody-Mediated Therapy in Gastric Cancer: Past, Present, and Future.
Antibody-Mediated Therapy in Gastric Cancer: Past, Present, and Future.
在胃癌治疗中，细胞毒性化疗的疗效有限，这在很大程度上由深刻的分子与生物学异质性所驱动。
胃癌细胞毒性化疗疗效有限，主要原因是肿瘤存在显著的分子和生物学异质性。相比之下，抗体介导疗法通过选择性分子靶向和免疫调节，开启了精准肿瘤治疗的新阶段。本综述全面回顾胃癌抗体疗法的发展，重点介绍早期突破、后续挫折及重塑治疗格局的近期进展。文章总结了目前针对HER2、VEGFR2、PD-1/PD-L1和CLDN18.2的标准方案，并讨论评估这些通路单克隆抗体的关键临床试验；同时介绍新兴治疗形式，包括新一代抗体药物偶联物（ADC）、双特异性抗体和嵌合抗原受体（CAR）T细胞疗法。曲妥珠单抗确立了HER2靶向治疗在胃癌中的地位，但曲妥珠单抗美坦新（T-DM1）试验失败后，该领域停滞近十年，直至曲妥珠单抗德鲁替康（T-DXd）显示显著临床活性并确立新的治疗标准。贝伐珠单抗未能改善生存，而抗VEGFR2抗体雷莫芦单抗则成为有效的二线治疗。基于CheckMate 649和KEYNOTE-811等里程碑试验，纳武利尤单抗和帕博利珠单抗等免疫检查点抑制剂已被纳入PD-L1阳性疾病的一线治疗。近期，靶向CLDN18.2的抗体佐妥昔单抗为经生物标志物筛选的患者拓展了治疗选择。此外，靶向TROP2的ADC、双特异性抗体和CAR-T细胞疗法等多种免疫策略正在积极进行临床开发。总之，以生物标志物为基础的抗体疗法进展正加快胃癌个体化治疗，并改善患者临床结局。
The limited efficacy of cytotoxic chemotherapy in the context of gastric cancer treatment is largely driven by profound molecular and biological heterogeneity. In contrast, the development of antibody-mediated therapies has ushered in a new era of precision oncology by enabling selective molecular targeting and immune modulation. This review includes a comprehensive overview of the evolution of antibody-based therapeutics in gastric cancer, highlighting early breakthroughs, subsequent setbacks, and recent advances that have reshaped the treatment landscape. We summarize the current standard regimens targeting HER2, VEGFR2, PD-1/PD-L1, and CLDN18.2 and examine pivotal clinical trials evaluating monoclonal antibodies directed against these pathways. We also discuss emerging therapeutic modalities, including next-generation antibody-drug conjugates (ADCs), bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapies. Trastuzumab first established HER2-targeted therapy in gastric cancer, but the failure of trastuzumab emtansine (T-DM1) led to a decade-long stagnation until the advent of trastuzumab deruxtecan (T-DXd), which demonstrated robust clinical activity and defined a new standard of care. While bevacizumab failed to improve survival, the anti-VEGFR2 antibody ramucirumab emerged as an effective second-line therapy. Immune checkpoint inhibitors, including nivolumab and pembrolizumab, have been incorporated into first-line treatment for PD-L1-positive disease based on landmark trials such as CheckMate 649 and KEYNOTE-811. More recently, the CLDN18.2-targeted antibody zolbetuximab has expanded therapeutic options for biomarker-selected patients. Concurrently, a diverse pipeline of immune-based strategies-such as TROP2-directed ADCs, bispecific antibodies, and CAR-T cell therapies-is undergoing active clinical development. Together, advances in biomarker-driven antibody therapeutics are accelerating personalized cancer care and improving clinical outcomes in patients with gastric cancer.
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