Paraneoplastic Autoimmune Neurological Syndromes and the Role of Immune Checkpoint Inhibitors

Harald Prüss,Sophie L. Duong

doi:10.1007/s13311-022-01184-0

Abstract

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.

Highlights

The adoption of novel cancer immunotherapies in general and notably the rise of immune checkpoint inhibitors (ICIs) in particular transform the oncologic therapeutic landscape [1]
Immune checkpoint inhibitors have become a crucial pillar of cancer therapies, yet they can be complicated by lifethreatening paraneoplastic neurological syndromes (PNSs) that bear the potential for severe and permanent disability
Diagnosis and improved treatment algorithms of ICI-triggered PNSs are invaluable for a favorable patient outcome and require knowledge of the diverse spectrum of clinical presentations

Summary

Introduction

The adoption of novel cancer immunotherapies in general and notably the rise of ICIs in particular transform the oncologic therapeutic landscape [1]. Recent years have shown that ICIs improve patient survival outcomes and achieve long-term remissions in multiple advanced malignancies such as metastatic melanoma, small-cell lung cancer (SCLC), non-small-cell lung cancer (NSCLC), and Hodgkin lymphoma, among others [1,2,3]. The clinical benefits of ICI therapy have increased the risk for severe immune-related adverse events (irAEs), resulting from the broad enhancement of endogenous immune responses. ICI-induced irAEs can affect any organ system, including the nervous system [5,6,7]. Neurological irAEs are clinically relevant as long-term sequelae remain in 40–60% of patients and 6–15% of all neurological toxicities are fatal [9,10,11]

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Conclusion