scholarly journals Immune Checkpoint Inhibitors for the Treatment of Central Nervous System (CNS) Metastatic Disease

2018 ◽  
Vol 8 ◽  
Author(s):  
Suneel D. Kamath ◽  
Priya U. Kumthekar
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Metastatic Disease ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors

scholarly journals Central Nervous System Demyelination Associated With Immune Checkpoint Inhibitors: Review of the Literature

2020 ◽  
Vol 11 ◽  
Author(s):  
Marcos C. B. Oliveira ◽  
Marcelo H. de Brito ◽  
Mateus M. Simabukuro
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Nervous System ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Case Reports ◽  
Cell Mediated Immune Response ◽  
Central Nervous System Demyelination

Immune checkpoint inhibitors (ICI) are a novel class of antineoplastic treatment that enhances immunity against tumors. They are associated with immune adverse events, and several neurological syndromes have been described, including multiple sclerosis and atypical demyelination. We performed a systematic literature review of case reports with neurological immune adverse events that presented with central nervous system demyelination, up to December 2019. We found 23 cases: seven with myelitis, four isolated optic neuritis, one neuromyelitis optica spectrum disorder, five multiple sclerosis, and six with atypical demyelination. Ipilimumab was the most frequently used ICI (11/23). The median time to develop symptoms from the onset of ICI was 6.5 weeks [range 1.0–43.0], and from last ICI dose was 14 days [range 0–161]. Anatomopathological examination was performed in four cases, with the finding of a T-cell mediated immune response. Outcomes were generally favorable after immunosuppression: 18 patients had improvement or a full recovery, three patients did not respond to treatment, three patients died, and in one, treatment was not reported. We describe the patients' clinical presentation, treatment administered, and outcomes. We further speculate on possible pathophysiological mechanisms and discuss potential treatments that may be worth investigating.

Central nervous system complications associated with immune checkpoint inhibitors

2020 ◽  
Vol 91 (7) ◽  
pp. 772-778 ◽  
Author(s):  
Alberto Vogrig ◽  
Sergio Muñiz-Castrillo ◽  
Bastien Joubert ◽  
Geraldine Picard ◽  
Veronique Rogemond ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Central Nervous System ◽  
Nervous System ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Small Cell Lung

ObjectiveTo describe the spectrum and outcome of central nervous system complications associated with immune checkpoint inhibitors (CNS-ICI).MethodsPatients with CNS-ICI were identified and their characteristics compared with ICI-related peripheral neuropathy (PN-ICI).ResultsWe identified 19 patients with CNS-ICI. The patients were receiving nivolumab (n=8), pembrolizumab (n=6), a combination of ipilimumab-nivolumab (n=3), ipilimumab-durvalumab (n=1), or atezolizumab (n=1). Underlying malignancies included non-small-cell lung cancer (n=8), melanoma (n=3), and other less common tumours (n=8). Neurological phenotypes were limbic encephalitis (n=8), meningoencephalitis (n=4) and cerebellitis (n=4). Two patients developed isolated confusion and one parkinsonism. Associated autoantibodies included onconeural (Ma2, n=7; Hu, n=1), astrocytic (glial fibrillar acidic protein, n=2) and neuronal surface (contactin-associated protein-like 2, n=1) specificities. ICIs were withheld and corticosteroid treatment was given in all cases. Five patients received intravenous immunoglobulin, two rituximab, one plasmapheresis and one infliximab. Overall, six patients died. Readministration of ICI was attempted in three patients, without further relapses. Non-small-cell lung cancer was significantly more frequent in patients with CNS-ICI (p<0.01), while melanoma and ipilimumab treatment were more common in PN-ICI (p<0.01 and p=0.01). Conversely, CNS-ICI cases were more frequently antibody-positive than PN-ICI (p<0.01) and showed a strong trend towards poorer outcome (p=0.053).ConclusionThree main clinical phenotypes characterise CNS complications of ICIs, each with distinct immunological background, disease course and response to treatment. Other clinical manifestations (including parkinsonism and steroid-responsive confusion) are also possible. Underlying cancers, antibody prevalence and outcome appear different from those of patients with PN-ICI.

scholarly journals Neurosarcoidosis following Immune Checkpoint Inhibition

2018 ◽  
Vol 11 (2) ◽  
pp. 521-526 ◽  
Author(s):  
Anastasie M. Dunn-Pirio ◽  
Suma Shah ◽  
Christopher Eckstein
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Relevant Literature ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Cns Involvement ◽  
Cns Metastases

Recently, immune checkpoint inhibitors have revolutionized cancer care by enhancing anti-tumor immunity. However, by virtue of stimulating the immune system, they can lead to immune-related adverse events (irAEs). Neurologic irAEs are uncommon but are becoming increasingly recognized and can be quite serious or even fatal. Furthermore, central nervous system (CNS) manifestations may be difficult to distinguish from CNS metastases, posing management challenges. Here, we describe a patient who developed exacerbation of sarcoidosis leading to CNS involvement following dual checkpoint blockade with nivolumab and ipilimumab for metastatic melanoma and review the relevant literature.

Central Nervous System Disorders Associated To Immune Checkpoint Inhibitors

2021 ◽  
Vol 17 ◽  
Author(s):  
Felipe Fanine de Souza ◽  
Julia Petry Trevisani ◽  
Letícia Caroline Breis ◽  
Luís Gustavo Marcelino Sizenando ◽  
Marco Antônio Machado Schlindwein ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Neurological Diseases ◽  
Cns Disorders ◽  
Central Nervous System Disorders ◽  
Wide Range ◽  
The Central Nervous System

: New therapies and alternatives for the containment of tumor progression are being proposed for the treatment of cancer. In this context, monoclonal therapies using immune checkpoint inhibitors (ICI) come as a therapeutic proposal. They are responsible for immunological control by blocking PD-1, PD-L1 and CTLA-4 molecules. However, among the effects caused by therapy, the use of medications is associated with neurological diseases reported as an adverse effect, affecting the central nervous system (CNS) and causing a wide range of symptoms. In this regard, the present bibliographic review presents the main CNS disorders associated with this therapy, in addition to the incidence, symptoms and treatment of these diseases.

Demyelinating disease of the central nervous system associated with Pembrolizumab treatment for metastatic melanoma

2018 ◽  
Vol 25 (7) ◽  
pp. 1005-1008 ◽  
Author(s):  
João Durães ◽  
Inês Coutinho ◽  
Angelina Mariano ◽  
Argemiro Geraldo ◽  
Maria Carmo Macário
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Demyelinating Disease ◽  
Checkpoint Inhibitors ◽  
Causative Role ◽  
First Case ◽  
The Central Nervous System

Immune checkpoint inhibitors are used in metastatic melanoma with good efficacy and safety profile. We report the first case of an inflammatory demyelinating disease of the central nervous system during treatment with Pembrolizumab and discuss the evidence in the literature supporting its causative role. The patient had a good clinical recovery after intravenous steroids, plasma exchange and discontinuation of Pembrolizumab. Due to the expected increase in the importance of immune checkpoint inhibitors in cancer treatment, it is important to be aware of neurological adverse events, as early treatment usually leads to good clinical responses.

scholarly journals Proposed diagnostic and treatment paradigm for high-grade neurological complications of immune checkpoint inhibitors

2018 ◽  
Vol 6 (5) ◽  
pp. 340-345 ◽  
Author(s):  
Dustin Anderson ◽  
Grayson Beecher ◽  
Nabeela Nathoo ◽  
Michael Smylie ◽  
Jennifer A McCombe ◽  
...  
Keyword(s):  
Nervous System ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Neurological Complications ◽  
High Grade ◽  
Small Cell Lung ◽  
Cytotoxic Lymphocyte ◽  
Programmed Cell Death 1 ◽  
Treatment Paradigm

Abstract Immune checkpoint inhibitors such as antibodies to cytotoxic lymphocyte-associated protein 4 (ipilimumab) and programmed cell-death 1 (pembrolizumab, nivolumab) molecules have been used in non-small cell lung cancer, metastatic melanoma, and renal-cell carcinoma, among others. With these agents, immune-related adverse events (irAEs) can occur, including those affecting the neurological axis. In this review, high-grade neurological irAEs associated with immune checkpoint inhibitors including cases of Guillain-Barré syndrome (GBS) and myasthenia gravis (MG) are analyzed. Based on current literature and experience at our institution with 4 cases of high-grade neurological irAEs associated with immune checkpoint inhibitors (2 cases of GBS, 1 case of meningo-radiculitis, and 1 case of myelitis), we propose an algorithm for the investigation and treatment of high-grade neurological irAEs. Our algorithm incorporates both peripheral nervous system (meningo-radiculitis, GBS, MG) and central nervous system presentations (myelitis, encephalopathy). It is anticipated that our algorithm will be useful both to oncologists and neurologists who are likely to encounter neurological irAEs more frequently in the future as immune checkpoint inhibitors become more widely used.

Neurotoxicity associated with immune checkpoint inhibitors: Systematic review and meta-analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15096-e15096
Author(s):  
Muhammad Zain Farooq ◽  
Sheeba Habeeb Ba Aqeel ◽  
Prasanth Lingamaneni ◽  
Shristi Upadhyay Banskota ◽  
Rayli Pichardo ◽  
...  
Keyword(s):  
Systematic Review ◽  
Nervous System ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Random Effect Model ◽  
Standard Of Care ◽  
Increased Risk ◽  
Statistical Heterogeneity

e15096 Background: Immune checkpoint inhibitors (ICI) are associated with multiple immune related adverse events (irAE). Moderate to severe neurotoxicity is reported in less than 1% of all patients treated with ICI. We performed a systematic review and meta-analysis to assess neurotoxicity associated with anti-PD-1/PD-L1 and anti-CTLA4 therapy. Methods: The Embase, Ovid, Pubmed and Scopus database were comprehensively searched by two independent reviewers, from inception to 2019, to include Phase II and III clinical trials reporting neurotoxicity with the combination of, or monotherapy with anti-PD-1/PD-L1 and/or anti-CTLA4 therapies. Our primary outcome was assessment of neurologic irAE of all grades. We divided neurotoxicity into two groups: peripheral nervous system (PNS) including peripheral neuropathy (PeN), fatigue, Guillain-Barre syndrome (GBS), myelitis; and central nervous system (CNS) including stroke, myasthenia gravis (MG), encephalopathy/encephalitis, altered mental status (AMS), decreased appetite and headache. Statistical heterogeneity was quantified using I2 statistics and publication bias was assessed with Eggers regression test. The estimates were reported as odds Ratio (OR) with 95% confidence intervals (CI) using random effect model. Results: A total of 2,876 full text articles retrieved in the initial database search were analyzed according to PRISMA guidelines. The final analysis included 39 trials, evaluating 10,595 patients in the control arm and 13,110 patients in the immunotherapy arm. All-grade neurotoxicity events with ICI were significantly lower compared to placebo or standard of care (OR 0.55, 95% CI 0.38-0.81, I2 96.82%, P < 0.001). Only significant CNS irAE observed was fatigue (OR 0.82, CI 0.71-0.96, I2 81.75%, P < 0.001). Other CNS irAE including AMS (OR 1.318, 95% CI 0.86-2.0, I2 0%, P = 0.442), encephalopathy/encephalitis (OR 1.36, 95% CI 0.38-4.96, I2 0%, P = 0.82) and seizures (OR 1.96, 95% CI 0.64-6.02, I2 0%, P = 0.56) had statistically non-significant increased risk in ICI group. Only one case of myelitis was reported in placebo group. The ICI arm had statistically significant lower rates of PeN (OR 0.28, CI 0.16-0.49, I2 87.31, P < 0.001). One trial reported 1 patient with MG and 5 trials reported 1 patient each of GBS in the ICI arm. Conclusions: Our meta-analysis concludes that use of ICI is associated with lower rate of neurotoxicity overall. Fatigue and PeN are lower with ICI compared to standard of care or placebo. Although, CNS irAE are increased with ICI, they do not reach statistical significance.

Association of systemic anticancer therapy with an increased risk of death in hospitalized COVID-19 positive oncology patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18594-e18594
Author(s):  
David Jacob Hermel ◽  
Samantha R. Spierling Bagsic ◽  
Munveer Singh Bhangoo ◽  
Kathryn Blount Bollin ◽  
James R. Mason ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Metastatic Disease ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Hematologic Malignancy ◽  
Anticancer Therapy ◽  
Cytotoxic Chemotherapy ◽  
Lung Involvement ◽  
Risk Of Death

e18594 Background: Malignancy is thought to be an independent risk factor for increased COVID-19 morbidity and mortality. However, neoplastic diseases encompass a heterogenous group of pathologic processes, and further stratification of those patients prone to severe disease is necessary. We sought to identify predictors of poor COVID-19 outcomes among hospitalized patients with malignancy. Methods: We retrospectively reviewed all patients with a diagnosis of hematologic and solid tumor malignancy within the regional Scripps Health hospital system in San Diego County from March 1, 2020 to January 5, 2021 with a PCR confirmed diagnosis of COVID-19. Cancer diagnoses were confirmed via manual chart review; in situ non-melanoma skin cancers were excluded. Only hospitalizations greater than one day were included in the analysis and readmissions were excluded. Outcomes of interest included admission to the ICU, intubation during hospitalization, and death. Associations between outcomes of interest and tumor types, metastatic disease (with or without lung involvement) and those receiving active systemic anticancer therapy (treatment within 3 months of admission) were determined using univariable logistic regression analyses. The study was approved by the Scripps Health Institutional Review Board. Systemic anticancer therapy included cytotoxic chemotherapy, immunomodulators, immune checkpoint inhibitors, and other targeted therapies. Results: Among a total of 2,771 hospitalized patients, 204 (7.36%) met inclusion criteria. The average age was 72.7 years, 48.5% were male, 33.3% were Hispanic and the average BMI was 27.5. The majority of patients (82.8%) had solid tumors, with the most prevalent being breast carcinoma (17.6%) and prostate carcinoma (17.2%). Overall, 21.9% had metastatic disease and 16% had lung involvement. 17.2% had been receiving active cancer systemic treatment. On univariate analysis, patients who were actively receiving treatment had an increased rate of death (37.1% vs 18.9%, OR: 2.5 (1.1-5.5) p= .021). Among patients receiving systemic anticancer therapy, 48.6% received cytotoxic chemotherapy, 5.7% immune checkpoint inhibitors, 22.9% immunomodulators, 17.1% molecularly targeted agents and 2.7% other agents. Moreover, there was a trend towards increased mortality in those with lung involvement (33.3% vs 17.6%, OR: 2.3 (0.9-5.7) p= .067) and those with hematologic malignancy (31.4% vs 20.1%, OR: 0.5 (0.2-1.3) p = 0.146). Conclusions: Among patients hospitalized with a diagnosis of cancer, systemic anticancer therapy was associated with a significantly increased odds of death. Other factors potentially increasing risk of death include hematologic malignancy and solid tumors with lung involvement. Further validation of these findings in a larger sample could impact therapeutic decision making during the COVID-19 pandemic.

scholarly journals Immune-Driven Pathogenesis of Neurotoxicity after Exposure of Cancer Patients to Immune Checkpoint Inhibitors

2020 ◽  
Vol 21 (16) ◽  
pp. 5774 ◽  
Author(s):  
Noelia Vilariño ◽  
Jordi Bruna ◽  
Foteini Kalofonou ◽  
Garifallia G. Anastopoulou ◽  
Andreas A. Argyriou
Keyword(s):  
Nervous System ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Clinical Importance ◽  
Complex Process ◽  
Wide Range ◽  
The Central Nervous System ◽  
Cancer Types

Over the last decade, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several cancer types. ICIs work through the blockage of immune inhibitory signals, while increasing the T-cell specific immune antitumoral response. However, due to the fact that ICIs’ mechanism of action is not tissue antigen-specific and not limited to the tumor microenvironment, the use of cancer immunotherapy can produce a broad range of immune-related adverse events (irAEs). Neurological immune-related adverse events (NirAEs) are rare (the overall incidence varies between 1% to 6%), and these adverse events mainly concern the peripheral nervous system, rather than the central nervous system. Due to their potential severity, which could cause interruptions to cancer treatment, NirAEs are of particular clinical importance. Currently, the pathogenesis of these complications is not completely understood, although T-cells seem to play a principal role. Nevertheless, the development of NirAEs is likely to be a multifactorial and complex process. This conclusion can be extracted from the wide range of neurological auto-inflammatory and autoimmune disorders triggered or exacerbated by ICIs, and the extensive variability of the limited histological findings reported. The aim of this review is to summarize the potential immune-driven pathological mechanisms of NirAEs.

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