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      Paraneoplastic Neurological Syndromes and Beyond Emerging With the Introduction of Immune Checkpoint Inhibitor Cancer Immunotherapy

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          Abstract

          Paraneoplastic neurological syndromes are more commonly seen with malignancies such as small cell lung cancer, thymoma, gynecological malignancies, and breast cancer as well as seminoma. With the introduction of immune checkpoint inhibitor (ICI) cancer immunotherapy we see an increase of autoimmune neurological complications in patients with malignancies not traditionally associated with paraneoplastic neurological syndromes, such as melanoma and renal cell carcinoma. Immune checkpoint inhibitors enhance antitumor immune responses resulting often in immune-related adverse effects that can affect any organ, including the central and peripheral nervous system, neuromuscular junction and muscle. Neurological complications are rare; neuromuscular complications are more common than central nervous system ones but multifocal neurological presentations are often encountered. The vast majority of neurological complications appear within 3 months of ICI initiation, but have been described even after ICI cessation. Neural autoantibody testing reveals autoantibodies in approximately half of the patients with CNS complications. Early suspicion and diagnosis is critical to avoid worsening and improve outcomes. Therapeutic strategies depend on the severity of the symptoms and initially typically involve discontinuation of ICI and high dose steroids. Further immunosuppression might be necessary. Outcomes are dependent on patient's characteristics and clinical presentations.

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          Most cited references129

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          The blockade of immune checkpoints in cancer immunotherapy.

          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer

            Nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, disrupts PD-1-mediated signaling and may restore antitumor immunity.
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              Cancer immunotherapy using checkpoint blockade

              The release of negative regulators of immune activation (immune checkpoints) that limit antitumor responses has resulted in unprecedented rates of long-lasting tumor responses in patients with a variety of cancers. This can be achieved by antibodies blocking the cytotoxic T lymphocyte antigen-4 (CTLA-4) or the programmed death-1 (PD-1) pathway, either alone or in combination. The main premise for inducing an immune response is the pre-existence of antitumor T cells that were limited by specific immune checkpoints. Most patients who have tumor responses maintain long lasting disease control, yet one third of patients relapse. Mechanisms of acquired resistance are currently poorly understood, but evidence points to alterations that converge on the antigen presentation and interferon gamma signaling pathways. New generation combinatorial therapies may overcome resistance mechanisms to immune checkpoint therapy.
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                Author and article information

                Contributors
                Journal
                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                1664-2295
                09 April 2021
                2021
                : 12
                : 642800
                Affiliations
                Departments of Neurology and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine , Rochester, MN, United States
                Author notes

                Edited by: Wei Qiu, Third Affiliated Hospital of Sun Yat-Sen University, China

                Reviewed by: Izumi Kawachi, Niigata University, Japan; Matteo Santoni, Marche Polytechnic University, Italy

                *Correspondence: Cristina Valencia-Sanchez valenciasanchez.cristina@ 123456mayo.edu

                This article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Neurology

                Article
                10.3389/fneur.2021.642800
                8062756
                33897597
                815c8c8d-6519-4532-9cb9-45e704c083c4
                Copyright © 2021 Valencia-Sanchez and Zekeridou.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 16 December 2020
                : 15 March 2021
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 129, Pages: 15, Words: 12981
                Funding
                Funded by: Mayo Foundation for Medical Education and Research 10.13039/100007048
                Categories
                Neurology
                Review

                Neurology
                cancer immunotherapy,autoimmune encephalitis,immune-related adverse events,myasthenia,myositis,paraneoplastic neurological syndromes

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