Lerch Magdalena, Ramanathan Sudarshini
Translational Neuroimmunology Group, Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
Translational Neuroimmunology Group, Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Department of Neurology and Concord Clinical School, Concord Hospital, Sydney, Australia.
Semin Immunol. 2025 Jun;78:101956. doi: 10.1016/j.smim.2025.101956. Epub 2025 Apr 27.
Cancer is a leading cause of morbidity and mortality worldwide. The development of immune checkpoint inhibitors (ICI) has revolutionised cancer therapy, and patients who were previously incurable can now have excellent responses. These therapies work by blocking inhibitory immune pathways, like cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death-1 (PD-1), its ligand PD-L1, and lymphocyte activation gene 3 (LAG-3); which leads to increased anti-tumour immune responses. However, their use can lead to the development of immune-related adverse events (irAEs), which may result in severe disability, interruption of cancer therapy, and even death. Neurological autoimmune sequelae occur in 1-10 % of patients treated with ICIs and can be fatal. They encompass a broad spectrum of diseases, may affect the central and the peripheral nervous system, and include syndromes like encephalitis, cerebellitis, neuropathy, and myositis. In some cases, neurological irAEs can be associated with autoantibodies recognising neuronal or glial targets. In this review, we first describe the key targets in ICI therapy, followed by a formulation of irAEs and their clinical presentations, where we focus on neurological syndromes. We comprehensively formulate the current literature evaluating cell surface and intracellular autoantibodies, cytokines, chemokines, leukocyte patterns, other blood derived biomarkers, and immunogenetic profiles; and highlight their impact on our understanding of the pathogenesis of neurological irAEs. Finally, we describe therapeutic pathways and patient outcomes, and provide an overview on future aspects of ICI cancer therapy.
癌症是全球发病和死亡的主要原因。免疫检查点抑制剂（ICI）的发展彻底改变了癌症治疗，以前无法治愈的患者现在可以有很好的反应。这些疗法通过阻断抑制性免疫途径发挥作用，如细胞毒性T淋巴细胞相关蛋白4（CTLA-4）、程序性细胞死亡蛋白1（PD-1）、其配体PD-L1和淋巴细胞激活基因3（LAG-3）；这会导致抗肿瘤免疫反应增强。然而，它们的使用可能会导致免疫相关不良事件（irAE）的发生，这可能会导致严重残疾、癌症治疗中断，甚至死亡。接受ICI治疗的患者中，1%-10%会出现神经自身免疫后遗症，且可能是致命的。它们涵盖广泛的疾病，可能影响中枢和周围神经系统，包括脑炎、小脑炎、神经病变和肌炎等综合征。在某些情况下，神经irAE可能与识别神经元或神经胶质靶点的自身抗体有关。在本综述中，我们首先描述ICI治疗中的关键靶点，然后阐述irAE及其临床表现，重点关注神经综合征。我们全面整理了当前评估细胞表面和细胞内自身抗体、细胞因子、趋化因子、白细胞模式、其他血液衍生生物标志物和免疫遗传图谱的文献；并强调它们对我们理解神经irAE发病机制的影响。最后，我们描述治疗途径和患者预后，并概述ICI癌症治疗的未来方向。
