Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
Office of Biotechnology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
Liver Int. 2018 Jun;38(6):976-987. doi: 10.1111/liv.13746. Epub 2018 Apr 24.
Immune checkpoint inhibitors (ICIs) block CTLA-4, PD-1 and PD-L1, or other molecules that control antitumour activities of lymphocytes. These products are associated with a broad array of immune-related toxicities affecting a variety of organs, including the liver. ICI-associated immune-mediated hepatitis (IMH) ranges in severity between mild and life-threatening and is marked by findings that bear both similarities as well as differences with idiopathic autoimmune hepatitis. Hepatotoxic events are often detected in clinical trials of ICIs that are powered for efficacy. Risk levels for ICI-induced liver injury may be impacted by the specific checkpoint molecule targeted for treatment, the ICI dose levels, and the presence of a pre-existing autoimmune diathesis, chronic infection or tumour cells which infiltrate the liver parenchyma. When patients develop liver injury during ICI treatment, a prompt assessment of the cause of injury, in conjunction with the application of measures to optimally manage the adverse event, should be made. Strategies to manage the risk of IMH include the performance of pretreatment liver tests with regular monitoring during and after ICI treatment and patient education. Using Common Terminology Criteria for Adverse Events developed at the National Cancer Institute to measure the severity level of liver injury, recommended actions may include continued ICI treatment with close patient monitoring, ICI treatment suspension or discontinuation and/or administration of corticosteroids or, when necessary, a non-steroidal immunosuppressive agent. The elucidation of reliable predictors of tumour-specific ICI treatment responses, as well as an increased susceptibility for clinically serious immune-related adverse events, would help optimize treatment decisions for individual patients.
免疫检查点抑制剂（ICIs）阻断 CTLA-4、PD-1 和 PD-L1 或其他控制淋巴细胞抗肿瘤活性的分子。这些产品与广泛的免疫相关毒性相关，影响多种器官，包括肝脏。ICI 相关的免疫介导性肝炎（IMH）的严重程度从轻到危及生命不等，其特征是既有与特发性自身免疫性肝炎相似的表现，也有不同的表现。在针对疗效的 ICI 临床试验中，经常会检测到肝毒性事件。ICI 诱导的肝损伤的风险水平可能受到治疗靶点的特定检查点分子、ICI 剂量水平以及存在预先存在的自身免疫倾向、慢性感染或浸润肝实质的肿瘤细胞的影响。当患者在 ICI 治疗期间发生肝损伤时，应迅速评估损伤的原因，并结合采取措施最佳地管理不良事件。管理 IMH 风险的策略包括在 ICI 治疗前进行肝脏检测，并在 ICI 治疗期间和之后定期监测，以及对患者进行教育。使用国家癌症研究所制定的不良事件通用术语标准来衡量肝损伤的严重程度，建议的措施可能包括继续 ICI 治疗并密切监测患者、暂停或停止 ICI 治疗以及/或给予皮质类固醇，或者在必要时给予非甾体类免疫抑制剂。阐明与肿瘤特异性 ICI 治疗反应相关的可靠预测因子以及对临床严重免疫相关不良事件的易感性增加，将有助于为个体患者优化治疗决策。
