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.