The application of immunological checkpoint inhibitors (ICIs) has modified many treatment strategies of malignant tumors, which has become a milestone in cancer therapy. The principle of action can be explained as "brake theory". After releasing the brakes by ICIs, unprecedented systemic toxicities, even some refractory and fatal immune-related adverse effects (irAEs) may develop. In this article, we summarized the recommended treatments of grade 3-4 severe irAEs in the latest European Society for Medical Oncology (ESMO), National Comprehensive Cancer Network (NCCN)/American Society of Clinical Oncology (ASCO), Society for Immunotherapy of Cancer (SITC) and Chinese Society of Clinical Oncology (CSCO) guidelines and consensus. We also performed a systemic review of case reports and reviews of irAEs up to May 20, 2019 in PubMed and Chinese journals. Successful applications of specific immunosuppressive drugs and stimulating factors beyond the above guidelines and consensus were supplemented and highlighted, including agents blocking interleukin 6 (IL-6), rituximab, anti-tumor necrosis factor-α (TNFα) monoclonal antibody (mAb), anti-integrin 4 mAb, Janus kinase inhibitors, thrombopoietin receptor agonists and antithymocyte globulin (ATG) etc. We put some concerns of using high-dose steroids for long-term, and emphasize the secondary infections, tumor progression, and unavailability of ICI re-challenge during steroid treatment. We propose the "De-escalation Therapy" principle for severe and refractory irAEs, and suggest that immunosuppressive drugs specifically targeting cytokines should be used as early as possible. Many irAEs in the era of immunotherapy are unprecedented compared with traditional chemotherapy and small-molecule targeted therapy, which is a big challenge to oncologists. Therefore, the establishment of multidisciplinary system is very important for the management of cancer patients.
【中文题目：危重及难治性免疫检查点抑制剂相关毒性反应诊治建议及探索】 【中文摘要：免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）的应用改写了很多恶性肿瘤的治疗策略，成为肿瘤治疗的又一个里程碑。ICIs作用原理可以理解为“刹车理论”，在“松开刹车”后会带来一系列的全身性毒副反应，其中部分可能为危重和难治性，甚至具有潜在致死性。本文对免疫相关不良事件（immune-related adverse effects, irAEs）相关的最新国内外指南及共识中关于3度-4度irAEs的诊治建议进行了汇总，包括欧洲肿瘤内科学会年会（European Society for Medical Oncology, ESMO）、美国国立综合癌症网络（National Comprehensive Cancer Network, NCCN）/美国临床肿瘤学会（American Society of Clinical Oncology, ASCO）、肿瘤免疫治疗学会（Society for Immunotherapy of Cancer, SITC）和中国临床肿瘤学会（Chinese Society of Clinical Oncology, CSCO）指南，并复习了2019年5月20日前公开发表的关于irAEs的个案报告和相关的综述文献后，对以上指南和共识中尚未纳入的3级-4级irAEs的诊治建议进行补充，重点介绍了特异性免疫抑制药物在不同的irAEs中成功应用的情况，包括抗白介素6（interleukin 6, IL-6）阻断、抗CD20单抗、抗肿瘤坏死因子α（tumor necrosis factor-α, TNFα）单抗、抗整合素4单抗、Janus激酶抑制剂、血小板生成素受体激动剂和抗胸腺细胞球蛋白（antithymocyte globulin, ATG）。本文对于类固醇激素在irAEs中超大剂量使用和升级使用及反复使用提出质疑，并强调应同时关注激素继发的感染、肿瘤进展和无法满足ICIs再挑战的等问题。本文提出对于危重和难治性irAEs的“降阶梯治疗”原则，建议应尽早使用细胞因子靶向药物这些特异性免疫抑制药物。免疫治疗时代诸多的irAEs是传统化疗及小分子靶向治疗时代不曾有过的，不断地挑战肿瘤科大夫的知识储备和临床基本技能。因此，建立肿瘤多学科讨论体系对于肿瘤患者的治疗管理极为重要。】 【中文关键词：免疫检查点抑制剂；免疫相关不良反应；难治性；危重性；降阶梯治疗】.
Keywords: De-escalation Therapy; Immune checkpoint inhibitor; Immunotherapy-related toxicities; Refractory; Severe.