Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, Yawkey 7E, Boston, MA, 02114, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Am J Clin Dermatol. 2019 Feb;20(1):41-54. doi: 10.1007/s40257-018-0389-y.
The recent development of effective immune checkpoint inhibition (ICI), first demonstrated in melanoma, has revolutionized cancer treatment. Monoclonal antibodies blocking the immune checkpoints cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 receptor (PD-1) have shown substantial clinical benefit in a subset of patients across tumor types and in both the metastatic and adjuvant settings. In this article, we review the interaction between the immune system and solid tumors, and describe modes of immune response failure and the physiologic role of immune checkpoints. We also review the known mechanisms of immune checkpoint inhibitors, focusing on US FDA-approved agents targeting CTLA-4 and PD-1. Within this framework, we classify hypothesized tumor intrinsic and extrinsic predictive markers for response and resistance to ICI, and map them to their putative underlying biological mechanism. Finally, we outline future directions in ICI, including the development of new therapeutic targets, rational combination therapies, integrated predictive models for individual patients to optimize therapy, and expansion into different disease types.
近年来，免疫检查点抑制（ICI）的有效发展，首先在黑色素瘤中得到证实，彻底改变了癌症治疗。阻断免疫检查点细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）和程序性死亡受体 1（PD-1）的单克隆抗体在多种肿瘤类型的部分患者中以及在转移性和辅助治疗环境中均显示出显著的临床获益。在本文中，我们回顾了免疫系统与实体瘤之间的相互作用，并描述了免疫反应失败的模式和免疫检查点的生理作用。我们还回顾了已知的免疫检查点抑制剂的机制，重点介绍了针对 CTLA-4 和 PD-1 的美国食品和药物管理局（FDA）批准的药物。在此框架内，我们对假设的肿瘤内在和外在的预测标志物进行分类，以预测对 ICI 的反应和耐药性，并将其映射到潜在的生物学机制上。最后，我们概述了 ICI 的未来发展方向，包括开发新的治疗靶点、合理的联合治疗、针对个体患者的综合预测模型以优化治疗，以及扩展到不同的疾病类型。
