Neurological adverse events of immune checkpoint inhibitors and the development of paraneoplastic neurological syndromes

Farina, Antonio; Villagrán-García, Macarena; Vogrig, Alberto; Zekeridou, Anastasia; Muñiz-Castrillo, Sergio; Velasco, Roser; Guidon, Amanda C; Joubert, Bastien; Honnorat, Jérôme

doi:10.1016/s1474-4422(23)00369-1

Cited by 19 publications

(26 citation statements)

References 103 publications

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“…Similarly to other non-neurological irAEs, some complications derive from a silent pre-existing and cancer-independent autoimmune condition, which may result in clinically manifest disease only after ICI-mediated immune activation in predisposed subjects [160]. By contrast, for other N-irAE, ICIs act as a second hit, boosting the immune response against antigens shared between cancer and neural tissue, as in classical paraneoplastic syndromes (PNS) [160][161][162]. Similarly to non ICI-related PNS, these "PNS-like" N-irAEs more frequently occur in association with lung cancer, explaining the greatest incidence of these phenotypes in the context of this tumor.…”

Section: Neurological Iraesmentioning

confidence: 99%

Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations

Casagrande,

Sopetto,

Bertalot

et al. 2024

Cancers

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The landscape of cancer treatment has undergone a significant transformation with the introduction of Immune Checkpoint Inhibitors (ICIs). Patients undergoing these treatments often report prolonged clinical and radiological responses, albeit with a potential risk of developing immune-related adverse events (irAEs). Here, we reviewed and discussed the mechanisms of action of ICIs and their pivotal role in regulating the immune system to enhance the anti-tumor immune response. We scrutinized the intricate pathogenic mechanisms responsible for irAEs, arising from the evasion of self-tolerance checkpoints due to drug-induced immune modulation. We also summarized the main clinical manifestations due to irAEs categorized by organ types, detailing their incidence and associated risk factors. The occurrence of irAEs is more frequent when ICIs are combined; with neurological, cardiovascular, hematological, and rheumatic irAEs more commonly linked to PD1/PD-L1 inhibitors and cutaneous and gastrointestinal irAEs more prevalent with CTLA4 inhibitors. Due to the often-nonspecific signs and symptoms, the diagnosis of irAEs (especially for those rare ones) can be challenging. The differential with primary autoimmune disorders becomes sometimes intricate, given the clinical and pathophysiological similarities. In conclusion, considering the escalating use of ICIs, this area of research necessitates additional clinical studies and practical insights, especially the development of biomarkers for predicting immune toxicities. In addition, there is a need for heightened education for both clinicians and patients to enhance understanding and awareness.

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Section: Neurological Iraesmentioning

confidence: 99%

Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations

Casagrande,

Sopetto,

Bertalot

et al. 2024

Cancers

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“…Biomedicines 2024, 12, 1319 2 of 22 Currently, four main categories of ICIs have been approved by the Food and Drug Administration (FDA), targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed death 1 (PD-1) receptor, programmed death ligand 1 (PD-L1), and lymphocyte activation gene 3 (LAG-3) [6]. Ipilimumab, targeting CTLA-4, was the first ICI approved for the treatment of metastatic melanoma, in 2011 [7].…”

Section: Introductionmentioning

confidence: 99%

“…Ipilimumab, targeting CTLA-4, was the first ICI approved for the treatment of metastatic melanoma, in 2011 [ 7 ]. To date, 14 ICIs are available for the treatment of various malignancies, including renal cell carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and advanced Hodgkin’s lymphoma among other tumors [ 6 , 8 ]. Additionally, numerous ongoing clinical trials are currently evaluating the safety and efficacy of novel therapeutic agents targeting both inhibitory and stimulatory ICPs, including the inducible T cell co-stimulator (ICOS), T cell Ig and ITIM domain (TIGIT), B cell and T lymphocyte attenuator (BTLA), T cell immunoglobulin and mucin domain containing 3 (TIM-3), and V-domain Ig-containing suppressor of T cell activation (VISTA) [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, numerous ongoing clinical trials are currently evaluating the safety and efficacy of novel therapeutic agents targeting both inhibitory and stimulatory ICPs, including the inducible T cell co-stimulator (ICOS), T cell Ig and ITIM domain (TIGIT), B cell and T lymphocyte attenuator (BTLA), T cell immunoglobulin and mucin domain containing 3 (TIM-3), and V-domain Ig-containing suppressor of T cell activation (VISTA) [ 8 ]. ICIs are being widely used for the treatment of advanced malignant diseases and, according to studies, they have significantly increased both survival and long-term remission rates [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…ICIs succeed in fighting advanced and aggressive types of malignancies, by fueling immune system responses at the cost of a wide spectrum of immune-related adverse events (irAEs), which might affect any organ or system, frequently mimicking classic autoimmune disorders [ 6 ]. About 90% of the individuals treated with ICIs have reported the occurrence of irAEs.…”

Section: Introductionmentioning

confidence: 99%

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Neurological Immune-Related Adverse Events Induced by Immune Checkpoint Inhibitors

Stavropoulou De Lorenzo,

Andravizou,

Alexopoulos

et al. 2024

Biomedicines

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The use of immune checkpoint inhibitors (ICIs) for the treatment of various advanced and aggressive types of malignancy has significantly increased both survival and long-term remission rates. ICIs block crucial inhibitory pathways of the immune system, in order to trigger an aggravated immune response against the tumor. However, this enhanced immune activation leads to the development of numerous immune-related adverse events (irAEs), which may affect any system. Although severe neurological irAEs are relatively rare, they carry a high disability burden, and they can be potentially life-threatening. Therefore, clinicians must be alert and act promptly when individuals receiving ICIs present with new-onset neurological symptoms. In this narrative review, we have collected all the currently available data regarding the epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of post-ICI neurological irAEs. This review aims to raise physicians’ awareness, enrich their knowledge regarding disease pathogenesis, and guide them through the diagnosis and management of post-ICI neurological irAEs.

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Paraneoplastic Calmodulin Kinase‐Like Vesicle‐Associated Protein (CAMKV) Autoimmune Encephalitis

Gilligan,

Lesnick,

Guo

et al. 2024

Annals of Neurology

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ObjectivesTo report an autoimmune paraneoplastic encephalitis characterized by immunoglobulin G (IgG) antibody targeting synaptic protein calmodulin kinase‐like vesicle‐associated (CAMKV).MethodsSerum and cerebrospinal fluid (CSF) samples harboring unclassified antibodies on murine brain‐based indirect immunofluorescence assay (IFA) were screened by human protein microarray. In 5 patients with identical cerebral IFA staining, CAMKV was identified as top‐ranking candidate antigen. Western blots, confocal microscopy, immune‐absorption, and mass spectrometry were performed to substantiate CAMKV specificity. Recombinant CAMKV‐specific assays (cell‐based [fixed and live] and Western blot) provided additional confirmation.ResultsOf 5 CAMKV‐IgG positive patients, 3 were women (median symptom‐onset age was 59 years; range, 53–74). Encephalitis‐onset was subacute (4) or acute (1) and manifested with: altered mental status (all), seizures (4), hyperkinetic movements (4), psychiatric features (3), memory loss (2), and insomnia (2). Paraclinical testing revealed CSF lymphocytic pleocytosis (all 4 tested), electrographic seizures (3 of 4 tested), and striking MRI abnormalities in all (mesial temporal lobe T2 hyperintensities [all patients], caudate head T2 hyperintensities [3], and cortical diffusion weighted hyperintensities [2]). None had post‐gadolinium enhancement. Cancers were uterine adenocarcinoma (3 patients: poorly differentiated or neuroendocrine‐differentiated in 2, both demonstrated CAMKV immunoreactivity), bladder urothelial carcinoma (1), and non‐Hodgkin lymphoma (1). Two patients developed encephalitis following immune checkpoint inhibitor cancer therapy (atezolizumab [1], pembrolizumab [1]). All treated patients (4) demonstrated an initial response to immunotherapy (corticosteroids [4], IVIG [2]), though 3 died from cancer.InterpretationCAMKV‐IgG is a biomarker of immunotherapy‐responsive paraneoplastic encephalitis with temporal and extratemporal features and uterine cancer as a prominent oncologic association. ANN NEUROL 2024

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Neurological adverse events of immune checkpoint inhibitors and the development of paraneoplastic neurological syndromes

Cited by 19 publications

References 103 publications

Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations

Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations

Neurological Immune-Related Adverse Events Induced by Immune Checkpoint Inhibitors

Paraneoplastic Calmodulin Kinase‐Like Vesicle‐Associated Protein (CAMKV) Autoimmune Encephalitis

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