Treatment with alemtuzumab induces depletion and reconstitution of circulating CD52+B and T lymphocytes, resulting in sustained changes of the adaptive immunity, which is thought to contribute to the clinical benefits in autoimmune disorders [123]. 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 DL-threo-2-methylisocitrate widespread use of ICIs in clinical practice. This review further discusses potential and evolving concepts of therapeutic monoclonal antibodies for the treatment of PNSs. == Supplementary Information == The online version contains supplementary material available at 10.1007/s13311-022-01184-0. Keywords:Paraneoplastic neurological syndromes, Immune checkpoint inhibitors, Neurological adverse events, Autoantibodies, Novel immunotherapies, Biologicals == 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 DL-threo-2-methylisocitrate 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 [13]. ICIs constitute monoclonal antibodies that block negative regulators of T cell activation, thus promoting T cell-mediated antitumor immune responses to overcome the evasive immune mechanisms of cancer cells [4]. Targets for the therapeutic blockade include the inhibitory immune checkpoints cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 receptor (PD-1) and its ligand PD-L1 [4]. 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 [57]. Neurological irAEs are rare complications with an estimated overall incidence of 3.8% with anti-CTLA-4 therapy, 6.1% with anti-PD-1 therapy, and 12% with a combination of both. Severe neurotoxicities occur in less than 1.0% of cases [8]. Yet, neurological irAEs are clinically relevant as long-term sequelae remain in 4060% of patients and 615% of all neurological toxicities are fatal [911]. Neurological symptoms usually develop within 3 months of ICI treatment [5,6,12]. The clinical features Rabbit polyclonal to PRKCH of neurological irAEs can be diverse with multifocal involvement, affecting any part of the nervous system. A subset of ICI-related neurotoxicities presents as PNSs. These neurotoxicities are of particular clinical concern for their often strikingly rapid clinical deterioration and severe, life-threatening manifestations that are associated with a poor neurological outcome if left untreated [1214]. Irrespective of ICI treatment, classical PNSs are defined as immune-mediated neurological disorders that can affect any part of the nervous system and demonstrate a tight association with cancer [15]. The widespread use of ICIs in oncology, especially in cancers known for DL-threo-2-methylisocitrate their paraneoplastic association (such as SCLC), is predicted to increase the incidence of PNSs [3,16,17]. The occurrence of these disorders within the context of such immunotherapies offers new perspectives on studying the immunological mechanisms underlying tumor immune surveillance and the collapse of immune tolerance resulting in PNSs. When PNSs arise as irAEs, it is important to exclude alternative diagnoses to pave the way for further management. The recognition of stereotyped neurological phenotypes, the detection of neuronal autoantibody biomarkers, and specific neuroimaging abnormalities are the pillars of establishing the diagnosis. This review provides an overview of distinct clinical features of PNSs in the framework of DL-threo-2-methylisocitrate ICI treatment and diagnostic approaches with focus on neuronal antibody association. This article further addresses proposed immunopathogenic principles of ICIs as triggers of PNSs, and the derived therapeutic strategies that are most pertinent to the treating neurologist. In view of the expanding indications of ICIs in oncology and the anticipated increased PNSs prevalence, this review aims to raise awareness among treating clinicians to timely identify these disorders, because if left untreated, PNSs are associated with high morbidity and mortality. == Cancer Immunity and Immunopathology of PNSs == PNSs are remote complications of systemic cancer that can affect every aspect of the nervous system, including the central nervous system (CNS), the peripheral nervous system, and the neuromuscular junction. These disorders are not directly attributable to the local effects and metastases of the underlying malignancy or indirectly caused by metabolic disturbances, coagulopathies, infections, or treatment-related side effects [15]. Instead, they commonly arise from a cross-reactive autoimmune response against shared autoantigens between cancer cells and the neuronal tissue (Fig.1) [18]. In a first step, ectopically expressed intracellular or cell surface neuronal antigens, including neoantigens resulting from genetic alterations in cancers cells, are released from necrotic tumor cells (Fig.1(1)). Antigen-presenting cells (APCs), such as dendritic cells, take up, process, and present these cancer-derived antigens on their surface via major histocompatibility complex.