A Systematic Review of the Mechanisms Involved in Immune Checkpoint Inhibitors Cardiotoxicity and Challenges to Improve Clinical Safety

Rubio-Infante, Néstor; Ramírez-Flores, Yoel Adbel; Castillo, Elena C.; Lozano, Omar; García‐Rivas, Gerardo; Torre‐Amione, Guillermo

doi:10.3389/fcell.2022.851032

Cited by 18 publications

(9 citation statements)

References 61 publications

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“…Studies have shown that the incidence of cardiotoxicity is higher with dual ICI therapy than the incidence treated with ICI monotherapy, either as single treatment or in combination with chemotherapy ( 26 ). The explanation of the increased cardiotoxicity of dual ICI therapy likely obeys the different signaling pathways inhibited by PD-1 and CTLA-4 molecules on T Cells ( 27 ). On the one hand, it prevents the binding of CTLA-4 and B7 molecules.…”

Section: Discussionmentioning

confidence: 99%

Cardiotoxicity of immune checkpoint inhibitors: A frequency network meta-analysis

Liu

Cheng

et al. 2022

Front. Immunol.

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Immune checkpoint inhibitors (ICIs) in combination withother anti-cancer treatments have been approved for a variety of cancers. While the difference in the incidence of cardiovascular adverse events has not been fully investigated. We aimed to assess the the differences in cardiotoxicity among cancer patients receiving different ICI therapies. PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov. websites were searched for all randomized controlled trials (RCTs) of ICI. The primary outcomes were any grade cardiotoxicity and Grade 3-5 cardiotoxicity, the secondary outcomes were any grade myocarditis and Grade 3-5 myocarditis, with sub-analyses based on cancer type and does of ICI. A systematic review and frequency network meta-analysis were then performed for cardiotoxicity events. 91 RCTs (n=52247) involving 12 treatment arms were finally included. We observed that PD-L1 + CTLA-4 had the highest risk among all therapies inducing any grade cardiotoxicity, and the differences were significant except PD-1 + CTLA-4, PD-1 + TTD and PD-L1 + TTD. In addition, CTLA-4 had a higher risk of Grade 3-5 cardiotoxicity than PD-1 and anit-PD-L1. For Grade 1-5 myocarditis and Grade 3-5 myocarditis, no significant difference was found among differences therapies. No differences were observed in subgroup analyses according to does and cancer type. There were differences in the incidence of cardiotoxicity among different ICI therapies. For ICI monotherapy, CTLA-4 may be linked to Grade 3-5 cardiotoxicity than PD-1 or PD-L1. For dual therapy, the cardiotoxicity of dual ICI therapy seems to be higher than that of chemotherapy or targeted therapy.

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Section: Discussionmentioning

confidence: 99%

Cardiotoxicity of immune checkpoint inhibitors: A frequency network meta-analysis

Liu

Cheng

et al. 2022

Front. Immunol.

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“…An unfavorable outcome, including death, intubation, or tracheostomy, was observed in 21 patients (35%), among which 14 (66.7%) died. [64][65][66] Therefore, the association of myasthenia with myositis in patients using PD-1 inhibitors should alert the clinicians to the risk of cardiac complications and initiate appropriate workup and aggressive immunosuppressive treatment. 67 Steroids (oral and intravenous) were the most frequent treatment (91%).…”

Section: Dovepressmentioning

confidence: 99%

Ocular Myasthenia Gravis: A Current Overview

Behbehani¹

2023

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Ocular myasthenia gravis (OMG) is a neuromuscular disease characterized by autoantibody production against postsynaptic proteins in the neuromuscular junction. The pathophysiological auto-immune mechanisms of myasthenia are diverse, and this is governed primarily by the type of autoantibody production. The diagnosis of OMG relies mainly on clinical assessment, the use of serological antibody assays for acetylcholine receptors (AchR), muscle-specific tyrosine kinase (MusK), and low-density lipoprotein 4 (LPR4). Other autoantibodies against post-synaptic proteins, such as cortactin and agrin, have been detected; however, their diagnostic value and pathogenic effect are not yet clearly defined. Clinical tests such as the ice test and electrophysiologic tests, particularly single-fiber electromyography, have a valuable role in diagnosis. The treatment of OMG is primarily through cholinesterase inhibitors (pyridostigmine), and steroids are frequently required in cases of ophthalmoplegia. Other immunosuppressive therapies include antimetabolites (azathioprine, mycophenolate mofetil, methotrexate) and biological agents such as B-cell depleting agents (Rituximab) and complement inhibitors (eculizumab). Evidence is scarce on the effect of immunosuppressive therapy on altering the natural course of OMG. Clinicians must be vigilant of a myasthenic syndrome in patients using immune-check inhibitors. Reliable and consistent biomarkers are required to assess disease severity and response to therapy to optimize the management of OMG. The purpose of this review is to summarize the current trends and the latest developments in diagnosing and treating OMG.

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“…While enhancing antitumor immunity, ICIs also have autoimmune effects on normal tissues, and such adverse events, including myocarditis, are called immune-related adverse events (irAEs) ( 5 , 6 ). A retrospective analysis reported that myocarditis occurred in 0.41% of patients receiving ICIs alone and 1.33% of patients receiving ICIs in combination, and mortality in patients with myocarditis is approximately 50%, making it the most lethal complication ( 7 , 8 ).…”

Section: Introductionmentioning

confidence: 99%

Role of mitochondrial metabolism in immune checkpoint inhibitors-related myocarditis

Zhang

Gan

Zhu

et al. 2023

Front. Cardiovasc. Med.

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BackgroundImmune checkpoint inhibitor-related myocarditis is the deadliest complication of immunotherapy. However, the underlying pathophysiological mechanisms of its occurrence and development remain unclear. Due to the long-term lack of effective early diagnosis and treatment options, it is of great significance to understand the pathophysiological mechanism of immune checkpoint inhibitor-related myocarditis.MethodsTissue samples from three patients with immune checkpoint inhibitor-related myocarditis and three control tissue samples were collected for protein analysis. Differentially expressed proteins were screened out using quantitative proteomics technology based on TMT markers. Protein–protein interaction (PPI) and Gene Ontology (GO) functional enrichment analyses of cross-factors were subsequently performed. Combined with the PD-L1 subcellular organelle- level protein interaction network, we searched for hub proteins involved in immune checkpoint inhibitor-related myocarditis and explored potential drug sensitivity and disease correlation.ResultsA total of 306 differentially expressed proteins were identified in immune checkpoint inhibitor-related myocarditis. Enrichment analysis showed that the differentially expressed proteins were closely related to mitochondrial metabolism. By analyzing mitochondria-related proteins and PD-L1-related proteins, we found four hub proteins, mammalian target of rapamycin (mTOR), Glycogen synthase kinase 3β (GSK3β), Protein tyrosine phosphatase non-receptor type 11 (PTPN11), and Mitofusin 2 (MFN2), indicating that they are closely related to immune checkpoint inhibitor-related myocarditis. Finally, we explored potential drugs for the treatment of immune checkpoint inhibitor-related myocarditis.ConclusionMitochondrial metabolism is involved in the process of immune checkpoint inhibitor-related myocarditis, and we identified four hub proteins, which may become new biomarkers for the early diagnosis and treatment of immune checkpoint inhibitor-related myocarditis.

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A Systematic Review of the Mechanisms Involved in Immune Checkpoint Inhibitors Cardiotoxicity and Challenges to Improve Clinical Safety

Cited by 18 publications

References 61 publications

Cardiotoxicity of immune checkpoint inhibitors: A frequency network meta-analysis

Cardiotoxicity of immune checkpoint inhibitors: A frequency network meta-analysis

Ocular Myasthenia Gravis: A Current Overview

Role of mitochondrial metabolism in immune checkpoint inhibitors-related myocarditis

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