Paraneoplastic Autoimmune Neurological Syndromes and the Role of Immune Checkpoint Inhibitors

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.

The role of neurologists in the era of cancer immunotherapy: Focus on CAR T-cell therapy and immune checkpoint inhibitors

“…Indeed, following treatment with ICIs, unrestrained T-cells may result in antigen-directed autoimmunity, either antibody- or T cell-mediated. Interestingly, several lines of evidence, including clinical phenotypes and serum/CSF autoantibody signature, substantiate the concept that these neurological complications represent either unleashed autoimmune or, less frequently, paraneoplastic neurological syndromes (PNS) ( 20 , 21 ). PNS comprise a heterogeneous group of immune-mediated neurological disorders, which may represent the heralding clinical presentation of a tumor ( 22 ).…”

Paraneoplastic Syndromes in Hodgkin’s Lymphoma

“…Theoretically, it does make sense that immunotherapy could amplify the immunological process leading to the development of PNSs, just as the antitumor effect is augmented, with uninhibited T cell activation [96]. Neurological adverse effects related to immunotherapy are particularly important as they are often complicated by long-term sequelae and can even be fatal [97]. A review by Farina et al investigates the occurrence of neurological immune-related adverse effects (n-irAE) in 147 patients with malignancies receiving immune checkpoint inhibitor therapy.…”

“…Recognizing stereotypical clinical syndromes, testing for onconeural antibodies, obtaining imaging to look for specific findings associated with neurological paraneoplastic syndromes, and conducting a thorough work-up to exclude alternate diagnoses including direct tumor-mediated pathology are all important steps in arriving at the diagnosis of immunotherapy-triggered PNSs [97]. This is an emerging area of medicine and we will likely see more studies in the next few years, which will hopefully allow us to better understand and manage these conditions.…”

Evaluation and management of acute high-grade immunotherapy-related neurotoxicity

“…Molecular mimicry or cross-reactivity among tumor antigens and neural antigens may lead to immune attack of the nervous system [ 32 ]. Neurological paraneoplastic syndromes (N-PNSs) can resemble NirAEs, and manifest onco-neuronal antibodies that also cross-react with neoplastic and neural antigens to cause damage [ [33] , [34] , [35] , [36] ]. In contrast with N-PNSs, NirAEs follow ICI treatment of cancer and are not necessarily associated with onco-neuronal autoantibodies [ [37] , [38] , [39] ].…”