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.

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.

scholarly journals Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not?

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 989
Author(s):  
Heidar J. Albandar ◽  
Jacob Fuqua ◽  
Jasim M. Albandar ◽  
Salahuddin Safi ◽  
Samuel A. Merrill ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Survival Outcomes ◽  
Limited Data ◽  
Risk Of Death ◽  
Survival Difference ◽  
Histopathologic Diagnosis ◽  
Cancer Types

Introduction: There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge. Methods: We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011–2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy. Results: Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former. Conclusions: Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.

Behcet’s-like syndrome following pembrolizumab: An immune-related adverse event associated with programmed death receptor-1 inhibitor therapy

2019 ◽  
Vol 26 (4) ◽  
pp. 995-999 ◽  
Author(s):  
Steffi Thomas ◽  
Chay Bae ◽  
Tabanor Joy-Ann ◽  
William Traverse
Keyword(s):  
Adverse Events ◽  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Death Receptor ◽  
Programmed Death ◽  
Organ Systems ◽  
Wide Range ◽  
The Right

Introduction The landscape for the treatment of metastatic melanoma has been revolutionized with the introduction immune checkpoint inhibitors. Immune checkpoint inhibitors have now become the standard of care for the treatment of cancers. These immune agents including programmed death receptor-1 inhibitors, programmed death-ligand 1 inhibitors and cytotoxic T-lymphocyte antigen-4 inhibitors have shown promising results but have been associated with numerous immune-related complications. Pembrolizumab, a programmed death receptor-1 inhibitor, has been associated with a number of immune-related adverse events affecting multiple organ systems including integument, ocular, endocrine, cardiovascular, pulmonary, renal, gastrointestinal, and musculoskeletal system. Case report We present a case of an 88-year-old Caucasian male with metastatic melanoma of the face with metastasis to the right fifth cranial nerve and into the right cavernous sinus. He underwent resection of the melanoma and was placed on pembrolizumab at 2 mg/kg every three weeks. Interestingly, 24 months on pembrolizumab therapy, he developed corneal erosions, oral and genital ulcerations. Management and outcome Patient completed his 24 months of pembrolizumab and was started on prednisone and colchicine with improvement in his symptoms. At his follow-up eight months, he had recurrence of an oral ulcer. Discussion Here we present a rare case of an elderly male on pembrolizumab who suffered from corneal erosions, oral and genital ulcers, a syndrome similar to Behcet’s disease. Given that pembrolizumab and other immune checkpoint inhibitors are being utilized in the treatment of cancers, physicians should be aware of the wide range immune-related adverse events including the possible Behcet’s-like syndrome presentation.

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.

scholarly journals Association of Immune Related Adverse Events With Efficacy of Immune Checkpoint Inhibitors and Overall Survival in Cancers: A Systemic Review and Meta-analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Yong Fan ◽  
Wenhui Xie ◽  
Hong Huang ◽  
Yunxia Wang ◽  
Guangtao Li ◽  
...  
Keyword(s):  
Overall Survival ◽  
Adverse Events ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Tumor Response ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Pooled Data ◽  
Cancer Types

ObjectivesImmune checkpoint inhibitors (ICIs) have brought impressive benefits to cancer patients, however often accompanied with immune-related adverse events (irAEs). We aimed to investigate the association of irAEs with efficacy and overall survival in cancer patients treated by ICIs, and further quantify the association by stratifying subgroups.MethodsPubMed, EMBASE and Cochrane library from database inception to 29 August 2019 were systematically searched. Articles reporting association of objective response rate (ORR), progression-free survival (PFS), overall survival (OS) with irAEs in cancer patients treated with approved ICIs were included. Adjusted odds ratios (OR) with 95% confidential intervals (CIs) were calculated for ORR, and hazard ratios (HR) were used for PFS and OS.ResultsA total of 52 articles comprising 9,156 patients were included. Pooled data demonstrated a statistically significant greater probability of achieving objective tumor response for patients with irAEs compared to those without (OR 3.91, 95% CI 3.05–5.02). In overall meta-analysis, patients who developed irAEs presented a prolonged PFS (HR 0.54; 95% CI 0.46–0.62) and OS (HR 0.51; 95% CI 0.41–0.59). More specifically, irAEs in certain cancer types (NSCLC and melanoma) and organs (skin and endocrine) were robustly associated with better clinical outcomes, while this association needs further verification regarding other tumors. High grade toxicities (G3–5) were not associated with a significantly favorable PFS or OS. Additionally, the association between irAEs and clinical benefit seemed to be more definite in patients receiving PD-(L)1 blockade than CTLA-4 blockade. Pooled data from landmark analyses displayed consistent results.ConclusionsThe occurrence of irAEs predicted improved tumor response and better survival in overall cancer patients treated with ICIs. Notably, the association stayed robust in certain cancer types (NSCLC and melanoma) and organ-specific irAEs (skin and endocrine).

Treatment-related adverse events of combination immune checkpoint inhibitors: Systematic review and meta-analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15060-e15060
Author(s):  
Robin Park ◽  
Laércio Lopes da Silva ◽  
Ivy Riano ◽  
Cagney Cristancho ◽  
Anwaar Saeed
Keyword(s):  
Adverse Event ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Related Adverse Event ◽  
Adverse Event Data ◽  
Cancer Types ◽  
Grade 3

e15060 Background: Despite increasing clinical experience with immune checkpoint inhibitors and the recent publication of clinical practice guidelines for managing treatment-related adverse events, precise and nuanced checkpoint inhibitor data in the setting of combination therapy is lacking. Herein we have conducted a systematic review and meta-analysis of treatment-related adverse event data from clinical trials evaluating combination immune checkpoint inhibitors. Methods: Studies published in PubMed, Embase, and Cochrane Database from conception to September 28, 2019 were included in the meta-analysis. Studies were eligible for inclusion if combination immune checkpoint inhibitor therapy was evaluated in advanced unresectable cancer and treatment-related adverse event data were available. For comparison of severity of adverse events in combination versus monotherapy, only the studies containing monotherapy arms as a control population were included, while all were included for calculation of pooled incidence of selected adverse events. Pooled risk ratio (RR) was used for the comparison of combination versus monotherapy and the logit transformed proportion for calculation of pooled incidence. Between-study risk of bias was evaluated using the Begg's funnel plot and Egger's regression test. Subgroup analysis was conducted by combination regimen, cancer type, and dosing regimen. Results: A total of 18 studies comprising 2767 patients across 10 cancer types were included in the final analysis. Combination ICI was associated with a slightly higher risk of all-grade adverse events (RR 1.07 [95% CI 1.03-1.11]) and markedly greater risk of grade 3 or higher adverse events (RR 2.21 [95% CI 1.57-3.10]) compared to monotherapy ICI. Subgroup analyses showed significant differences in risk of grade 3 or higher adverse events between treatment type (PD-1+CTLA-4 and PD-L1+CTLA-4), among cancer types, and among dosing regimens (N1I3, N3I1 and D20T1). Incidence of all-grade adverse events was 0.905 [95% CI 0.842-0.945] and grade 3 or higher events/all-grade adverse events was 0.396 [95% CI 0.315-0.483]. The most common all-grade TRAEs were diarrhea/colitis, fatigue/asthenia, nausea/vomiting, rash, and pruritis. Conclusions: Combination ICI therapy has a significantly different treatment-related adverse event profile compared to monotherapy.

scholarly journals The Role of Cytokines in Predicting the Response and Adverse Events Related to Immune Checkpoint Inhibitors

2021 ◽  
Vol 12 ◽  
Author(s):  
Min Wang ◽  
Xiaoyang Zhai ◽  
Ji Li ◽  
Jingyuan Guan ◽  
Shuhui Xu ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Tnf Α ◽  
Wide Range

Recently, the overall survival (OS) and progression-free survival (PFS) of patients with advanced cancer has been significantly improved due to the application of immune checkpoint inhibitors (ICIs). Low response rate and high occurrence of immune-related adverse events (irAEs) make urgently need for ideal predictive biomarkers to identity efficient population and guide treatment strategies. Cytokines are small soluble proteins with a wide range of biological activity that are secreted by activated immune cells or tumor cells and act as a bridge between innate immunity, infection, inflammation and cancer. Cytokines can be detected in peripheral blood and suitable for dynamic detection. During the era of ICIs, many studies investigated the role of cytokines in prediction of the efficiency and toxicity of ICIs. Herein, we review the relevant studies on TNF-α, IFN-γ, IL-6, IL-8, TGF-β and other cytokines as biomarkers for predicting ICI-related reactions and adverse events, and explore the immunomodulatory mechanisms. Finally, the most important purpose of this review is to help identify predictors of ICI to screen patients who are most likely to benefit from immunotherapy.

scholarly journals Neurotoxicities associated with immune checkpoint inhibitor therapy

2020 ◽  
Vol 19 ◽  
Author(s):  
Zhiyi Zhao ◽  
Chunlin Zhang ◽  
Lian Zhou ◽  
Pan Dong ◽  
Lei Shi
Keyword(s):  
Nervous System ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Peripheral Neuropathies ◽  
The Central Nervous System ◽  
Checkpoint Inhibitor Therapy ◽  
Promising Treatment

: Immune checkpoint inhibitors (ICIs) have recently been used as a promising treatment for cancer while their toxicity and immune-related side effects can involve in any organ, including the nervous system. In contrast to other immune-related adverse events (irAEs), neurological irAEs (nAEs) are rare, with varying incidence and symptoms complexity. Although nAEs are uncommon, they can sometimes be severe and even lead to death. However, little attention has been paid to nAEs and the literatures are mostly clinical reports with only a few cases. We therefore conducted the present review with the aim of providing a comprehensive introduction of nAEs. In this review, we summarized various nAEs, including meningitis, encephalitis and hypophysitis in the central nervous system, and myositis, myasthenia gravis and peripheral neuropathies in the peripheral system. We also reviewed the current diagnosis and treatment methods for nAEs commonly used in clinical practice. In addition, we discussed about potential mechanisms regarding nAEs and proposed the possible approaches to preventing the risk of nAEs in patients treated with ICIs. There's still a lot to learn, such as whether and why patients with nAEs respond better to ICI-therapy. The mechanisms and significance of nAEs need to be fully clarified to address these issues and to optimize the treatment strategy.

scholarly journals Immune checkpoint inhibitor-induced aseptic meningitis and encephalitis: a case-series and narrative review

2021 ◽  
Vol 12 ◽  
pp. 204209862110047
Author(s):  
Laure Thouvenin ◽  
Timothée Olivier ◽  
Giuseppe Banna ◽  
Alfredo Addeo ◽  
Alex Friedlaender
Keyword(s):  
Adverse Events ◽  
Aseptic Meningitis ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Case Series ◽  
Plain Language ◽  
Wide Range

Background: Along with the increasing use of immune checkpoint inhibitors comes a surge in immune-related toxicity. Here, we review the currently available data regarding neurological immune adverse events, and more specifically aseptic meningitis and encephalitis, and present treatment and diagnostic recommendations. Furthermore, we present five cases of immunotherapy-induced aseptic meningitis and encephalitis treated at our institution. Recent findings: Neurological immune-related adverse events, including aseptic meningitis and encephalitis, secondary to checkpoint inhibitors are a rare but complex and clinically relevant entity, comprising a wide range of diseases, most often presenting with symptoms with a wide range of differential diagnoses. Our case-series highlights the challenges of such entities and the importance of properly identifying and managing aseptic meningitis and encephalitis. Summary: Checkpoint inhibitor-induced meningoencephalitis warrants prompt investigations and treatment. Properly diagnosing aseptic meningitis, encephalitis, or mixed presentations may guide the treatment decision, as highlighted by our case-series. After rapid exclusion of alternative diagnoses, urgent corticosteroids are the therapeutic backbone but this could change in favour of highly specific cytokine-directed treatment options. Plain language summary Aseptic meningitis and encephalitis with immune checkpoint inhibitors: a single centre case-series and review of the literature Over the course of the past decade, checkpoint inhibitors have revolutionized cancer care. With their favourable toxicity profile and potential for durable and deep responses, they have become ubiquitous across the field of oncology. Furthermore, combination checkpoint inhibitors are also gaining ground, with increased efficacy and, unfortunately, immune-related toxicity. While there are guidelines based on extensive clinical experience for frequent adverse events, uncommon entities are less readily identified and treated. Neurological immune-related adverse events secondary to checkpoint inhibitors are a rare but complex entity, comprising a wide range of diseases, most often presenting with aspecific symptoms. In this paper, we discuss a single institution case-series of patients with autoimmune aseptic meningitis and encephalitis, and we perform a narrative literature review on this subject. We conclude with our treatment recommendations based on available evidence.

Mechanisms and clinical manifestations of cardiovascular toxicities associated with immune checkpoint inhibitors

2021 ◽  
Vol 135 (5) ◽  
pp. 703-724
Author(s):  
Alan H. Baik ◽  
Katy K. Tsai ◽  
David Y. Oh ◽  
Mandar A. Aras
Keyword(s):  
Immune System ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Clinical Manifestations ◽  
Immune System Activation ◽  
Wide Range ◽  
Anti Cancer

Abstract Immunotherapies have greatly expanded the armamentarium of cancer-directed therapies in the past decade, allowing the immune system to recognize and fight cancer. Immune checkpoint inhibitors (ICIs), in particular, have revolutionized cancer treatment and have demonstrated survival benefit in numerous types of cancer. These monoclonal antibodies increase anti-cancer immunity by blocking down-regulators of adaptive immunity, including cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand (PD-L1), resulting in anti-tumor activity. As ICIs increase immune system activation, they can cause a wide range of inflammatory side effects, termed immune-released adverse events. Though these toxicities can affect nearly any organ, the most fatal toxicity is myocarditis. Here, we discuss the diverse spectrum of cardiovascular toxicities associated with ICI use. In addition, we provide insight and future directions on mechanisms and treatments for immune-related adverse events (irAEs) involving the myocardium, pericardium, vasculature, and conduction system.

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