Michot J M, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, Berdelou A, Varga A, Bahleda R, Hollebecque A, Massard C, Fuerea A, Ribrag V, Gazzah A, Armand J P, Amellal N, Angevin E, Noel N, Boutros C, Mateus C, Robert C, Soria J C, Marabelle A, Lambotte O
Department of Medicine Oncology, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Internal Medicine and Clinical Immunology Department, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Bicêtre, F-94275 Le Kremlin Bicêtre, France.
Department of Medicine Oncology, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France.
Eur J Cancer. 2016 Feb;54:139-148. doi: 10.1016/j.ejca.2015.11.016. Epub 2016 Jan 5.
Cancer immunotherapy is coming of age; it has prompted a paradigm shift in oncology, in which therapeutic agents are used to target immune cells rather than cancer cells. The first generation of new immunotherapies corresponds to antagonistic antibodies that block specific immune checkpoint molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1) and its ligand PD-L1. Targeting these checkpoints in patients living with cancer had led to long-lasting tumour responses. By unbalancing the immune system, these new immunotherapies also generate dysimmune toxicities, called immune-related adverse events (IRAEs) that mainly involve the gut, skin, endocrine glands, liver, and lung but can potentially affect any tissue. In view of their undisputed clinical efficacy, anti-CTLA-4 and anti-PD-1 antibodies are entering in the routine oncological practice, and the number of patients exposed to these drugs will increase dramatically in the near future. Although steroids can be used to treat these IRAEs, the associated immunosuppression may compromise the antitumour response. Oncologists must be ready to detect and manage these new types of adverse events. This review focuses on the mechanisms of IRAE generation, putative relationship between dysimmune toxicity and antitumour efficacy, as a basis for management guidelines.
癌症免疫疗法正在走向成熟；它促使肿瘤学领域发生了范式转变，即治疗药物用于靶向免疫细胞而非癌细胞。第一代新型免疫疗法对应于拮抗抗体，这些抗体可阻断特定的免疫检查点分子，如细胞毒性T淋巴细胞相关抗原4（CTLA-4）、程序性细胞死亡蛋白（PD-1）及其配体PD-L1。在癌症患者中靶向这些检查点已导致持久的肿瘤反应。通过使免疫系统失衡，这些新型免疫疗法还会产生免疫失调毒性，称为免疫相关不良事件（IRAEs），主要累及肠道、皮肤、内分泌腺、肝脏和肺部，但可能潜在地影响任何组织。鉴于其无可争议的临床疗效，抗CTLA-4和抗PD-1抗体正在进入常规肿瘤学实践，并且在不久的将来，接触这些药物的患者数量将大幅增加。尽管类固醇可用于治疗这些IRAEs，但相关的免疫抑制可能会损害抗肿瘤反应。肿瘤学家必须准备好检测和管理这些新型不良事件。本综述重点关注IRAE产生的机制、免疫失调毒性与抗肿瘤疗效之间的假定关系，作为管理指南的基础。
