Duong Sophie L, Prüss Harald
Department of Neurology and Experimental Neurology, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany.
German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117, Berlin, Germany.
Neurotherapeutics. 2022 Apr;19(3):848-863. doi: 10.1007/s13311-022-01184-0. Epub 2022 Jan 18.
The introduction of immune checkpoint inhibitors (ICIs) in oncologic therapies has led to a paradigm shift in cancer treatment. ICIs have increased the overall survival in patients with malignant melanoma, small-cell lung cancer, and many other tumor entities. Despite their clinical benefits, these novel cancer immunotherapies can induce neurological immune-related adverse events (irAEs). Such immune-mediated complications can manifest within the spectrum of paraneoplastic neurological syndromes (PNSs). PNSs are rare immune-mediated complications of systemic cancers that can involve every aspect of the nervous system. The emergence of PNSs with ICI treatment opens further pathways to study the complex immunopathological interplay of cancer immunity, cross-reactive neurological autoimmune phenomena, and effects of ICIs on the immune system. ICI-induced PNSs comprise a diverse antibody repertoire and phenotypic spectrum with severe and life-threatening disease progression in some cases. Timely diagnosis and urgent interventions are pivotal for a favorable neurologic and oncologic outcome. This review focuses on the pathogenesis of cancer immunotherapy and the disruption of immune tolerance in PNSs and provides an overview of the most pertinent clinical manifestations and principles of diagnostic and therapeutic managements in light of the expected increase in PNSs due to the widespread use of ICIs in clinical practice. This review further discusses potential and evolving concepts of therapeutic monoclonal antibodies for the treatment of PNSs.
免疫检查点抑制剂（ICIs）在肿瘤治疗中的引入引发了癌症治疗的范式转变。ICIs提高了恶性黑色素瘤、小细胞肺癌和许多其他肿瘤实体患者的总生存率。尽管具有临床益处，但这些新型癌症免疫疗法可诱发神经免疫相关不良事件（irAEs）。此类免疫介导的并发症可表现为副肿瘤性神经综合征（PNSs）。PNSs是系统性癌症罕见的免疫介导并发症，可累及神经系统的各个方面。ICI治疗引发的PNSs为研究癌症免疫、交叉反应性神经自身免疫现象以及ICIs对免疫系统的影响之间复杂的免疫病理相互作用开辟了新途径。ICI诱导的PNSs具有多样的抗体库和表型谱，在某些情况下会出现严重且危及生命的疾病进展。及时诊断和紧急干预对于良好的神经和肿瘤学结局至关重要。本综述重点关注癌症免疫治疗的发病机制以及PNSs中免疫耐受的破坏，并鉴于临床实践中ICI广泛使用导致PNSs预期增加的情况，概述了最相关的临床表现以及诊断和治疗管理原则。本综述还讨论了治疗PNSs的治疗性单克隆抗体的潜在和不断发展的概念。
