Neurologic Autoimmunity in the Era of Checkpoint Inhibitor Cancer Immunotherapy

Abstract

Some can initiate complement activation (with or without membrane lysis), antigen internalization, functional blockade, opsonization/phagocytosis, or antibody-dependent cell-mediated cytotoxicity. Because they are functionally monovalent, IgG4 antibodies are incapable of activating complement, internalizing antigen, opsonizing membranes, or mediating antibody-dependent cell-mediated cytotoxicity. Therapeutic blockade of this negative regulatory pathway unleashes the primed effector T-cell response at the level of the tumor itself.12,24 As anticipated from the past 3 decades of observations in neurology practice, an emerging adverse event with all checkpoint inhibitors, used singly and in combination, is neurologic autoimmunity involving multiple levels of the neuraxis.12,25-30 Experiments in a transgenic mouse model confirmed the potential of checkpoint inhibitor therapy to trigger paraneoplastic neurologic autoimmunity when the cancer expresses a pertinent onconeural antigen. Examples of these neurologic disorders are POEMS syndrome (polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes), myelin-associated glycoprotein IgM neuropathy, and amyloidosis associated with monoclonal gammopathy of unknown significance.68 On the other hand, cerebellar degeneration and limbic encephalitis occurring with hematologic malignancies are neural antigen-specific autoimmune disorders.69 Neuronal autoantigens identified to date include Delta/notch-like epidermal growth factor-related receptor (DNER, the antigen of PCA-Tr- IgG), mGluR1, and mGluR type 5.68 Unlike other paraneoplastic autoimmune neurologic disorders, symptoms and signs generally follow cancer diagnosis.69 A rare autoimmune synaptopathy targeting dipeptidyl-peptidase- like protein-6 (DPPX) has been associated with B-cell malignancies.70'71 This severe encephalopathy is generally responsive to early-initiated immunotherapy and is often accompanied by profound dysautonomia and gastrointestinal dysmotility.70-72 AUTOIMMUNE NEUROLOGIC DISORDERS IN THE ERA OF CHECKPOINT INHIBITOR CANCER IMMUNOTHERAPY Checkpoint inhibitor therapy is an emerging and underappreciated cause of neurologic autoimmunity. Abbreviations and Acronyms: AChR = acetylcholine receptor; AMPAR = a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ANNA = antineuronal nuclear autoantibody; CARP VIII = carbonic anhydrase VIII; CNS = central nervous system; Caspr2 = contactin-associated protein-2; CRMP5 = collapsin response-mediator protein 5; CTLA4 = cytotoxic T lymphocyte-associated antigen 4; DNER = ô Notch-like epidermal growth factor-related receptor; DPPX = dipeptidyl-peptidase-like protein-6; GABA = g-aminobutyric acid; GFAP = glial fibrillary acidic protein; HA = hemagglutinin antigen; LGI1 = leucine-rich, glioma-inactivated 1 protein; mGluR = metabotropic glutamate receptor; MHC1 = major histocompatibility complex class I; MHC2 = major histocompatibility complex class II; NMDAR = N-methyl-D-aspartate receptor; PCA = Purkinje cell cytoplasmic autoantibody; PD1 = programmed cell death 1; PDL1 = programmed cell death ligand 1; SCLC = small cell lung carcinoma; VGCC = voltage-gated calcium channel Correspondence: Address to Anastasia Zekeridou, MD, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (Zekeridou.