Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of several malignancies, with improved survival. These monoclonal antibodies target immune checkpoints, including cytotoxic T-lymphocyte-associated protein 4 (ipilimumab and tremelimumab), programmed death 1 (nivolumab, pembrolizumab, cemiplimab, and dostarlimab), programmed death ligand 1 (atezolizumab, avelumab, and durvalumab), and lymphocyte activation gene 3 (relatlimab), and effectively augment the immune response against tumor cells. Releasing the brakes on the immune system has consequences, however, in the form of immune-related adverse events (irAEs), which may affect any organ. Neurologic irAEs represent 1%-3% of all irAEs, with immune-mediated myopathy (ICI myopathy) being the most common manifestation. Recent large patient series and systematic reviews have established the key features and highlighted new insights into ICI myopathy. ICI myopathy is characterized by an acute or subacute onset of oculobulbar and/or proximal limb weakness, with or without associated respiratory insufficiency and myocarditis. Creatine kinase elevation is common. Oculobulbar presentations with or without respiratory failure may be misattributed to neuromuscular junction disorders, particularly because acetylcholine receptor antibodies are present in up to 40% of patients; however, an electrodiagnostic evidence of a defect of neuromuscular transmission is often absent even in patients with severe weakness, highlighting that the myopathic process is the driving force behind these presentations. Muscle histopathology commonly demonstrates a unique signature of multifocal clusters of necrotic and regenerating fibers, differentiating ICI myopathy from other autoimmune myopathies. Transcriptomic analysis has uncovered distinct subgroups within ICI myopathy, revealing varying degrees of type 1 and type 2 interferon pathway activation alongside notable upregulation of the interleukin (IL)-6 pathway in affected muscle tissue. This discovery presents a promising avenue for intervention through the use of therapies that suppress the interferon pathway and target IL-6 or its receptor. Despite clinical improvements with immunomodulatory therapy, with corticosteroids the mainstay of treatment, mortality remains high, particularly in those with associated myocarditis or respiratory failure requiring intubation, where mortality occurs in up to 50%. ICI withdrawal can lead to cancer progression and death, highlighting a need for improved approaches to ICI rechallenge, performed in limited patients with variable success to date.

中文翻译：

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免疫检查点抑制剂肌病：癌症免疫疗法的双刃剑。


免疫检查点抑制剂 （ICI） 疗法彻底改变了几种恶性肿瘤的治疗，提高了生存率。这些单克隆抗体靶向免疫检查点，包括细胞毒性 T 淋巴细胞相关蛋白 4（ipilimumab 和 tremelimumab）、程序性死亡 1（nivolumab、pembrolizumab、cemiplimab 和 dostarlimab）、程序性死亡配体 1（atezolizumab、avelumab 和 durvalumab）和淋巴细胞活化基因 3（relatlimab），并有效增强针对肿瘤细胞的免疫反应。然而，释放免疫系统的刹车会产生免疫相关不良事件 （irAE） 的形式，这可能会影响任何器官。神经系统 irAE 占所有 irAE 的 1%-3%，其中免疫介导的肌病 （ICI myopathy） 是最常见的表现。最近的大型患者系列和系统评价确定了 ICI 肌病的关键特征并强调了新的见解。ICI 肌病的特征是急性或亚急性发作的眼球和/或近端肢体无力，伴有或不伴有相关的呼吸功能不全和心肌炎。肌酸激酶升高很常见。伴或不伴呼吸衰竭的眼球表现可能被误认为是神经肌肉接头疾病，特别是因为高达 40% 的患者存在乙酰胆碱受体抗体;然而，即使在严重无力的患者中，也往往不存在神经肌肉传递缺陷的电诊断证据，这突出表明肌病过程是这些表现背后的驱动力。肌肉组织病理学通常表现出坏死和再生纤维多灶性簇的独特特征，可将 ICI 肌病与其他自身免疫性肌病区分开来。 转录组学分析发现了 ICI 肌病中不同的亚组，揭示了不同程度的 1 型和 2 型干扰素通路激活，以及受影响肌肉组织中白细胞介素 （IL）-6 通路的显着上调。这一发现为通过使用抑制干扰素途径和靶向 IL-6 或其受体的疗法进行干预提供了一种有前途的途径。尽管免疫调节疗法在临床上有所改善，皮质类固醇是主要治疗方法，但死亡率仍然很高，尤其是在需要插管的相关心肌炎或呼吸衰竭患者中，死亡率高达 50%。ICI 戒断可导致癌症进展和死亡，这凸显了改进 ICI 再挑战方法的必要性，该方法在迄今为止成功率不一的有限患者中进行。