4.5　Adverse Reactions and Management

Immune checkpoint inhibitors activate anti-tumor defenses either through the disruption of inhibitory interactions between antigen-presenting cells and T lymphocytes at so-called checkpoints(anti-PD-1/PD-L1, anti-CTLA-4, anti-TIM-3, anti-LAG-3) or else through the stimulation of activating checkpoints (CD27, CD40, GITR, CD137).They are now used to treat various types of cancer, including lung cancer, renal cell carcinoma, Merkel cell carcinoma, Hodgkin’s lymphoma,and urothelial carcinoma and special groups of patients, e.g., patients with microsatellite instability.In patients with metastatic melanoma, the anti-CTLA-4 antibody ipilimumab, the anti-PD-1 antibodies nivolumab and pembrolizumab, and combination therapy with ipilimumab and an anti-PD-1 antibody can prolong survival and induce response rates of 19%, 36%-44%, and 58%-61%, respectively.Severe and even life-threatening side effects (classified according to the Common Terminology Criteria for Adverse Events [CTCAE]; grade 3/4) arise in 17%-21% of patients receiving anti-PD-1 monotherapy, 20%-28% of those receiving ipilimumab, 45% of those receiving ipilimumab (1 mg/kg) plus pembrolizumab, and 59% of those receiving approved combination therapy with ipilimumab (3 mg/kg) and nivolumab [29].

Immune checkpoint inhibitors often induce autoimmune side effects, which can affect all organ systems.These differ from the corresponding spontaneously occurring autoimmune diseases in many ways, including phenotypically, histologically, and serologically.The mechanisms of autoimmune side effects include the activation of T lymphocytes with infiltration of the organ in question, direct binding of the checkpoint inhibitor with activation of complement (CTLA-4 expression in the pituitary gland), and immune reactions due to soluble factors (autoantibodies,cytokines).Moreover, the intestinal microbiome seems to influence the development of side effects.No predictive factors for the appearance of side effects have yet been identified [30].(https://www.daowen.com)

Common side effects include colitis, hepatitis, skin reactions, and endocrinopathies (thyroiditis or hypophysitis); rarer ones are myositis, cardiomyositis, and neurological side effects.These side effects are usually readily controllable.Checkpoint inhibitor treatment must be discontinued because of side effects in 7%-12% of patients receiving anti-PD-1 therapy, 9%-16% of those receiving ipilimumab therapy, and 39% of those receiving combination therapy.Treatmentassociated deaths have been reported in the setting of both primary and adjuvant treatment [31].

The early initiation of corticosteroid treatment can shorten the duration of autoimmune side effects and prevent complications.Algorithms for side-effect management, including recommended courses of action, are now available.Checkpoint inhibitors are no less effective in melanoma patients who stop taking them because of side effects.In 25% of patients treated with ipilimumab and nivolumab, side effects arose in more than one organ system.Thus, patients presenting with symptoms in one organ system must be carefully checked for side effects elsewhere.This article is based on information from pertinent publications retrieved by a literature search in PubMed and on an evaluation of a side-effect registry [32].