Immune Checkpoint Inhibitor-related Myocarditis Research Articles

Analysis of risk factors and establishment of prediction model for immune checkpoint inhibitor related myocarditis and major adverse cardiovascular events

Objectives: To explore the risk factors of major adverse cardiovascular events (MACEs) in immune checkpoint inhibitor (ICI) related myocarditis and establish a predictive model. Methods: This was a retrospective case-control study. Tumor patients diagnosed with ICI related myocarditis in the First Affiliated Hospital of Guangzhou Medical University from May 2019 to August 2023 were selected and divided into non-MACE group and MACE group based on whether MACE occurred. Clinical and imaging data of the two groups were collected. Univariate and multivariate logistic regression models were used to analyze the risk factors for MACE in patients with ICI related myocarditis. According to the results of multivariate logistic regression analysis, R 4.1.0 software was used to construct the MACE risk prediction model for these patients and draw a nomogram. The receiver operating characteristic curve was used to evaluate the prediction ability of the prediction model. Results: A total of 35 patients with ICI related myocarditis, aged (63.9±8.2) years, were included, including 28 males (80%). There were 18 patients in the non-MACE group and 17 patients in the MACE group. Multivariate logistic regression analysis showed that elevated neutrophil to lymphocyte ratio (OR=1.115, 95%CI 1.007-1.235, P=0.036) and ST-T segment changes (OR=24.942, 95%CI 1.239-502.194, P=0.036) were risk factors for MACE in patients with ICI related myocarditis. The receiver operating characteristic curve indicated that the area under the curve of the prediction model was 0.967 (95%CI 0.916-1.000, P<0.001), with a sensitivity of 88.2% and specificity of 100%, demonstrating good predictive ability. Conclusion: Elevated neutrophil to lymphocyte ratio and ST-T segment change are independent risk factors for MACE in patients with ICI related myocarditis. Risk prediction model based on the above two indicators can assist in the early identification and individualized intervention of ICI related myocarditis patients.

Prognostic value of neutrophil-to-lymphocyte ratio and cardiac troponin I in patients with immune checkpoint inhibitors-related myocarditis

Abstract Background Over the past decade, immune checkpoint inhibitors (ICIs) have significantly transformed cancer treatment. However, ICIs inevitably may cause a spectrum of immune-related adverse events, among which cardiovascular toxicity, particularly myocarditis, while infrequent, has garnered increasing attention due to its high fatality rate. Purpose We executed a multicenter study aimed at characterizing ICI-related myocarditis and risk factors influencing its prognosis. Methods The study included patients with ICIs-associated myocarditis at four medical centers in China from January 28, 2019 to June 15, 2023. Logistic regression was performed to explore the risk factors for the development of severe myocarditis. Receiver operating characteristic curves were conducted to assess the diagnostic abilities of biomarkers to distinguish severe myocarditis, and the performance and calibration were evaluated using Hosmer-Lemeshow test. Cox regression analysis was employed to investigate the influential risk factors affecting the prognosis of ICI-related myocarditis. Kaplan-Meier survival curve analyses were conducted to assess the differences in survival times among different myocarditis groups. Results 35 ICIs-associated myocarditis patients were identified. 21 patients (60%) were classified as severe myocarditis, and they presented higher cardiac troponin I (cTnI) levels (P=0.013), higher N-terminal pro-B-type natriuretic peptide levels (P=0.031), higher creatine kinase (CK) levels (P=0.018), higher CK-MB levels (P=0.026), and higher neutrophil to lymphocyte ratio (NLR) levels (P=0.016) compared to non-severe myocarditis patients. Multivariate logistic regression showed that cTnI (adjusted odds ratio: 1.021, 95% confidence interval (CI): 1.002-1.039, P=0.03) and NLR (adjusted odds ratio: 1.890, 95% CI: 1.026-3.483, P=0.041) were the independent risk factors of ICI-associated severe myocarditis. The receiver operating characteristic curve showed an area under curve of 0.765 (95% CI: 0.601 to 0.929, P=0.013) for cTnI, and 0.773 for NLR (95% CI: 0.597 to 0.948, P=0.016). Multivariate COX regression showed that NLR (adjusted hazard ratio: 1.189, 95% CI: 1.028-1.376, P=0.020) and pneumonitis (adjusted hazard ratio: 8.142, 95% CI: 1.191-55.651, P=0.032) were the independent prognostic risk factor associated ICI- related myocarditis. Further Kaplan-Meier survival curve analysis showed that the survival rate among patients without pneumonitis and with low level of NLR significantly outstripped that of patients with pneumonitis (P=0.015) and high level of NLR (P=0.024). Conclusions As independent risk factors for the development of ICI-associated severe myocarditis, cTnI and NLR demonstrated a promising predictive utility for the identification of ICI-associated severe myocarditis. NLR and the presence of pneumonitis were identified as independent risk factors that significantly impacted the prognosis of ICI-related myocarditis.

Nomograms based on ratio indexes to predict severity and prognosis in immune checkpoint inhibitors-related myocarditis: a retrospective analysis

PurposeImmune checkpoint inhibitors-related myocarditis (ICI-M) is one of the immune-related adverse events (irAEs), which is rare and highly lethal. This study aimed to establish nomograms based on ratio biomarkers to predict the severity and prognosis of ICI-M.MethodsWe retrospectively examined patients with advanced cancers who were also diagnosed with ICI-M at the Fourth Hospital of Hebei Medical University. The patients of ICI-M were divided into mild and severe groups and a 40-day following up was carried out. The major adverse cardiovascular events(MACEs) were regarded as the endpoint. Nomogram-based models were established and validated.ResultsSeventy-seven patients were involved, including 31 severe cases(40.3%). Lactate dehydrogenase-to-albumin ratio(LAR) combined with the change rate from baseline to onset of LAR(▵\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\ riangle$$\\end{document}LAR) which performed best to diagnose the severe ICI-M was identified to establish the nomogram-based model. The bootstrap-corrected concordance index [0.752 95% confidence interval (CI): 0.635-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$-$$\\end{document}0.866] and calibration plot with good degree of fitting confirmed this diagnostic model. Neutrophil-to-high-density lipoprotein cholesterol ratio(NHR) and LAR were also screened into the nomogram-based model for 40-day MACEs after ICI-M, which performed well by validating for concordance index(0.779 95% CI: 0.677-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$-$$\\end{document}0.865)and calibration plots after being bootstrap-corrected. Moreover, a ≥\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\ge$$\\end{document}101% increase in LAR significantly separated patients in MACE-free survival.ConclusionRatio indexes at onset and their change rates from baseline showed good diagnostic value for the severity of ICI-M and prognostic value for subsequent MACEs, particularly LAR, NHR and their change rates. The nomogram-based models of ratio indexes could provide a potential choice for early detection and monitor of the severe ICI-M and subsequent MACEs.Graphical abstract

Abstract 7474: T-cell responses across heart, blood, and tumor in patients with immune checkpoint inhibitor-related myocarditis (irMyocarditis)

Abstract Introduction: Immune checkpoint inhibitor (ICI)-related myocarditis (irMyocarditis) is a potentially lethal complication of ICI use that is characterized by the presence of clonally expanded T cells in the heart. The antigens recognized by these expanded intracardiac T-cell clones and their relationships to T-cell clones in the blood and tumors of irMyocarditis patients are poorly understood. Methods: Paired single-cell RNA sequencing (scRNA-seq) and T-cell receptor (TCR) sequencing was performed on heart tissue (n = 13) and peripheral blood from patients with irMyocarditis (n = 25) and ICI-treated controls (n = 28) using the 10X Chromium (10X Genomics) system. TCR-β chain sequencing was performed (Adaptive Biotechnologies) on four autopsy cases of patients with available scRNA-seq data and irMyocarditis heart, tumor, and histologically normal tissue. An established high-throughput protocol was used to screen expanded intracardiac TCRs against candidate antigens (Oliveira G, et al. Nature 2021). Briefly, full-length TCRs were cloned, transduced into donor T cells, and screened against autologous or major histocompatibility complex (MHC) Class I-matched antigen presenting cell lines pulsed with peptide pools that covered the full length of the ⍺-myosin, troponin-I, and troponin-T proteins alongside pools of common viral antigens and appropriate controls. Results: scRNA-seq data showed that TCRs shared between heart and blood are predominantly found in circulating CD8 T cell subsets as compared to circulating CD4 T cell subsets. The gene expression patterns of these shared T-cell clones in circulation appear distinct in fatal and non-fatal irMyocarditis patients, with shared T-cell clones in fatal cases expressing cycling markers (MKI67, STMN1) and the chemokine receptor CXCR3. TCR-β chain sequences most enriched in irMyocarditis tissue relative to control tissues were distinct from those enriched in tumor tissues, and their full-length TCR sequences could be recovered from scRNA-seq data. In total, 52 cardiac-expanded TCRs across eight donors were screened against candidate antigens. None of the screened TCRs recognized the putative cardiac autoantigens. Conclusions: T-cell clones expanded in irMyocarditis are shared in circulation, where the gene expression of these clones may help to distinguish fatal from non-fatal irMyocarditis. TCRs enriched in irMyocarditis appear to be largely distinct from those enriched in tumor and likely recognize currently unknown cardiac autoantigens. Citation Format: Steven Blum, Daniel A. Zlotoff, Neal P. Smith, Isabela J. Kernin, Swetha Ramesh, Giacomo Oliveira, Leyre Zubiri, Joshua Caplin, Nandini Samanta, Sidney Martin, Mike Wang, Alice Tirard, Pritha Sen, Yuhui Song, Katherine Xu, Jaimie L. Barth, Kamil Slowikowski, Mazen Nasrallah, Jessica Tantivit, Kasidet Manakongtreecheep, Benjamin Y. Arnold, John McGuire, Alexander B. Afeyan, Christopher J. Pinto, Daniel McLoughlin, Monica Jackson, PuiYee Chan, Aleigha Lawless, William A. Michaud, Tatyana Sharova, Linda T. Nieman, Justin F. Gainor, Dejan Juric, Mari Mino-Kenudsen, Ryan J. Sullivn, Genevieve M. Boland, James R. Stone, Catherine J. Wu, Molly F. Thomas, Tomas G. Neilan, Kerry L. Reynolds, Alexandra-Chloé Villani. T-cell responses across heart, blood, and tumor in patients with immune checkpoint inhibitor-related myocarditis (irMyocarditis) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7474.

Single-cell RNA sequencing reveals the altered innate immunity in immune checkpoint inhibitor-related myocarditis.

Myocarditis has emerged as a rare but lethal immune checkpoint inhibitor (ICI)-associated toxicity. However, the exact mechanism and the specific therapeutic targets remain underexplored. In this study, we aim to characterise the transcriptomic profiles based on single-cell RNA sequencing from ICI-related myocarditis. Peripheral blood mononuclear cell (PBMC) samples were collected from four groups for single-cell RNA sequencing: (1) patients with newly diagnosed lung squamous cell carcinoma before treatment (Control Group); (2) patients with lung squamous cell carcinoma with PD-1 inhibitor therapy who did not develop myocarditis (PD-1 Group); (3) patients during fulminant ICI-related myocarditis onset (Myocarditis Group); and (4) Patients with fulminant ICI-related myocarditis during disease remission (Recovery Group). Subcluster determination, functional analysis, single-cell trajectory and cell-cell interaction analysis were performed after scRNA-seq. Bulk-RNA sequencing was performed for further validation. Our results revealed the diversity of cellular populations in ICI-related myocarditis, marked by their distinct transcriptional profiles and biological functions. Monocytes, NKs as well as B cells contribute to the regulation of innate immunity and inflammation in ICI-related myocarditis. With integrated analysis of scRNA-seq and bulk sequencing, we identified S100A protein family as a potential serum marker for ICI-related myocarditis. Our study has created a cell atlas of PBMC during ICI-related myocarditis, which would shed light on the pathophysiological mechanism and potential therapeutic targets of ICI-related myocarditis in continuous exploration.

Protective effect of low‐intensity pulsed ultrasound on immune checkpoint inhibitor-related myocarditis via fine-tuning CD4+ T-cell differentiation

PurposeImmune checkpoint inhibitors (ICIs) have transformed traditional cancer treatments. Specifically, ICI-related myocarditis is an immune-related adverse event (irAE) with high mortality. ICIs activate CD4+ T-lymphocyte reprogramming, causing an imbalance between Th17 and Treg cell differentiation, ultimately leading to myocardial inflammatory damage. Low-intensity pulsed ultrasound (LIPUS) can limit inflammatory responses, with positive therapeutic effects across various cardiovascular inflammatory diseases; however, its role in the pathogenesis of ICI-related myocarditis and CD4+ T-cell dysfunction remains unclear. Accordingly, this study investigated whether LIPUS can alleviate ICI-related myocarditis inflammatory damage and, if so, aimed to elucidate the beneficial effects of LIPUS and its underlying molecular mechanisms.MethodsAn in vivo model of ICI-related myocarditis was obtained by intraperitonially injecting male A/J mice with an InVivoPlus anti-mouse PD-1 inhibitor. LIPUS treatment was performed via an ultrasound-guided application to the heart via the chest wall. The echocardiographic parameters were observed and cardiac function was assessed using an in vivo imaging system. The expression of core components of the HIPPO pathway was analyzed via western blotting.ResultsLIPUS treatment reduced cardiac immune responses and inflammatory cardiac injury. Further, LIPUS treatment alleviated the inflammatory response in mice with ICI-related myocarditis. Mechanistically, in the HIPPO pathway, the activation of Mst1–TAZ axis improved autoimmune inflammation by altering the interaction between the transcription factors FOXP3 and RORγt and regulating the differentiation of Treg and Th17 cells.ConclusionLIPUS therapy was shown to reduce ICI-related myocarditis inflammatory damage and improve cardiac function, representing an exciting finding for irAEs treatment.

The role of circulating biomarkers in predicting the 30-day mortality of immune checkpoint inhibitors-related myocarditis: a retrospective cohort study.

Immune checkpoint inhibitors-related myocarditis (ICIs-M) is a rare and highly lethal immune-related adverse events (irAEs) in common irAEs. This study aims to find circulating biomarkers that can reflect disease state and prognosis accurately. 48 patients with ICIs-M were enrolled according to the diagnostic criteria for ICIs-related myocarditis. For all enrolled patients, valuable information was extracted retrospectively from the medical system, mainly including demographic information, tumor information and laboratory examination. The follow-up period was defined as 30days after the first diagnosis of ICIs-M. In this study, the 30-day mortality rate of ICIs-M was 24.4%. After adjusting for potential confounding factors using multivariate analysis tools, we demonstrated the excellent performance of biomarkers in predicting 30-day mortality in patients with ICIs-M, including PLT (hazard ratio (HR),1.07; 95% confidence interval (95%CI),1.01-1.14; p = 0.028), ALT (HR, 1.23; 95%CI, 1.06-1.41; p = 0.005), AST(HR,1.06; 95%CI,1.01-1.10; p = 0.015), LDH (HR,1.15; 95%CI, 1.04-1.26; p = 0.004), troponin I(HR, 1.44; 95%CI, 1.09-1.89; p = 0.009), PLR (blood plate/lymphocyte) (HR, 1.04; 95% CI,1.01-1.07; p = 0.024), LAR (lactate dehydrogenase/albumin) (HR, 1.05; 95%CI,1.01-1.09; p = 0.012), and AAR (aspartate transaminase/albumin) (HR, 1.18; 95%CI, 1.00-1.39; p = 0.048). The analysis of the receiver operating characteristic showed that biomarkers with area under curve (AUC) greater than or equal to 0.80 were LDH (cutoff value,724.5; AUC, 0.86;95%CI, 0.75-0.97), LAR (cutoff value,18.11; AUC, 0.87;95%CI, 0.76-0.97), troponin I (cutoff value,0.87; AUC, 0.80;95%CI, 0.62-0.99), and AAR(cutoff value,1.52; AUC, 0.80;95%CI, 0.61-0.98). LDH, LAR, troponin I, and AAR are a group of promising biomarkers that demonstrate excellent predictive ability in predicting the 30-day mortality rate of immune-related myocarditis.

Abstract 18700: Immune Checkpoint Inhibitor-Related Myocarditis and Overlapping Syndromes

Background: Immune checkpoint inhibitor (ICI)-related myocarditis is a rare adverse effect of ICI's. When accompanied by overlapping myasthenia gravis, prognosis is worsened. While established guidelines aid in the treatment of ICI-associated adverse events, management of overlapping syndromes is complex and challenging. Case description: A 66-year-old man with metastatic renal cell carcinoma recently started on ipilimumab and nivolumab presented with dizziness and diplopia. He had high-grade atrioventricular (AV) block with junctional escape. He had elevated troponin, transaminases, and creatinine kinase. Coronary angiogram showed no evidence of obstructive coronary artery disease. A permanent pacemaker was placed. Cardiac MRI showed no specific features of myocarditis, though quality was limited by pacemaker artifact; left ventricular ejection fraction was 29%. MRI of the orbits showed no signs of extraocular myositis. Acetylcholine receptor (AChR) antibody and muscle-specific kinase (MuSK) antibody was negative. Given ongoing suspicion for ICI-associated adverse events, the patient underwent endomyocardial biopsy. This revealed lymphocytic myocarditis, confirming the diagnosis of ICI-related myocarditis. Despite improvement of troponin, transminases, and creatinine kinase, he developed progressive weakness, dysphagia, and respiratory failure, and died one month after initial presentation. Discussion: We highlight a case of ICI-related myocarditis presenting as high-grade AV block with concurrent hepatitis, myositis, and probable serologic-negative myasthenia gravis (MG). Overlapping syndromes are common in patients with exposure to ICI's, and are associated with significantly higher mortality. Although steroids are first-line for treating ICI-associated adverse events including myocarditis, they can initially lead to acute worsening of MG symptoms. While our patient had laboratory and biomarker improvement of his myocarditis, hepatitis, and myositis, he developed progressive weakness and respiratory failure. Our case highlights the complexity and challenges of managing ICI-related myocarditis and overlapping syndromes, including MG, and its poor prognosis despite prompt treatment.

Immune-Checkpoint Inhibitor-Related Myocarditis: Where We Are and Where We Will Go.

Immune checkpoint inhibitors (ICIs) are specific monoclonal antibodies directed against inhibitory targets of the immune system, mainly represented by programmed death-1 (PD1) ligand-1 (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4), thus enabling an amplified T-cell-mediated immune response against cancer cells. These drugs have significantly improved prognosis in patients with advanced metastatic cancer (e.g., melanoma, non-small cell lung cancer, renal cell carcinoma). However, uncontrolled activation of anti-tumor T-cells could trigger an excessive immune response, possibly responsible for multi-organ damage, including, among others, lymphocytic myocarditis. The incidence of ICIs-induced myocarditis is underestimated and the patients affected are poorly characterized. The diagnosis and management of this condition are mainly based on expert opinion and case reports. EKG and ultrasound are tests that can help identify patients at risk of myocarditis during treatment by red flags, such as QRS complex enlargement and narrowing of global longitudinal strain (GLS). Therapy of ICI-related myocarditis is based on immunosuppressors, monoclonal antibodies and fusion proteins. A future strategy could involve the use of microRNAs. This review considers the current state of the art of immune-related adverse cardiovascular events, focusing on histological and clinical features, diagnosis and management, including current treatments and future pharmacological targets.

Cardiotoxicity is mediated by the NLRP3 inflammasome in hiPSC-derived endothelial cells from patients with immune checkpoint inhibitor-related myocarditis

In association with immune checkpoint inhibitors (ICI) anticancer therapy, myocarditis (ICI-M), have emerged with a mortality rate reaching 50%. The IFN-γ pathway and inflammasome regulatory proteins seem to be specifically involved in ICI-M, but the mechanism of action remains unclear. In the cardiovascular system, the endocardial and vascular endothelium is involved in the regulation of the contractile function of cardiomyocytes. Our hypothesis is that the cardiotoxicity induced by the infiltration of immune cells into the myocardium is partly due to an exacerbation of inflammasome activation in endothelial cells, which subsequently affects the cardiomyocytes function. Our aim is to characterize the role of endothelial cells in ICI-related myocarditis in a unique model of induced pluripotent stem cells (hiPSC)-derived cardiac cells. The hiPSC were generated from melanoma patients who received anti-PD-1/anti-CTLA-4 immunotherapy and followed at the Cardio-Oncology Centre (North Hospital, Marseille). Twelve hiPSC clones were generated from patients who developed myocarditis (ICI-M, 6 clones from 3 patients), and patients who did not develop cardiotoxicity (non-ICI-M, 6 clones from 3 patients). hiPSC-derived endothelial cells (hiPSC-EC) were differentiated from hiPSC clones and stimulated by 10 ng/mL of IFN-γ during 48 h. IFN-γ induced a decrease in cell viability, as well as an increase in the expression of transcripts of genes associated with the JAK/STAT and NLRP3 inflammasome pathways in hiPSC-EC. However, the decrease in cell viability was significantly greater in hiPSC-EC from the ICI-M group compared to the non-ICI-M group. IFN-γ activation of inflammatory intracellular signalling is greater in the ICI-M group, in particular overexpression of the jak1, jak2, stat3 and gbp6 transcripts. At the protein level, in this ICI-M group, the IFN-γ-induced increase of MHC-I and PD-L1 is greater than in the non-ICI-M group. IFN-γ stimulation revealed specific regulations in endothelial cells derived from hiPSC clones from patients with ICI-related myocarditis. We are now analysing the apoptotic and inflammatory activity of hiPSC-EC by real-time microscopy monitoring of caspases (Incucyte S3) and by assaying pro-inflammatory molecules in the supernatants (ELISA). This study will allow to establish the role played by endothelial cells in cardiac toxicity induced by ICI immunotherapy.

Role of mitochondrial metabolism in immune checkpoint inhibitors-related myocarditis.

Immune 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. Tissue 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. A 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. Mitochondrial 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.

Protective Effect of Crocin on Immune Checkpoint Inhibitors-Related Myocarditis Through Inhibiting NLRP3 Mediated Pyroptosis in Cardiomyocytes via NF-κB Pathway.

PurposeImmune checkpoint inhibitors (ICIs)-related myocarditis is now one of the most critical immune-related adverse effects (irAEs) in tumor immunotherapy, which has raised great concern in cardio-oncology. The pathogenesis involved in cardiac injury remains elusive. Crocin, the main component of saffron, has shown distinct functions in cardioprotective and anti-inflammation properties. We therefore aimed to investigate the potential effect of crocin on the protection of ICIs-related myocarditis and its underlying molecular mechanism.MethodsWe immunized the BALB/c mice with murine cardiac troponin I (cTnI) peptide and additionally gave anti-mouse programmed death 1 (PD-1) to induce the mouse model of ICIs-related myocarditis. Mice were treated with crocin at different dosages. In vitro, HL-1 cells were pre-incubated with crocin at different concentrations and then stimulated with lipopolysaccharide (LPS). Myocardial contractile functions, myocardial inflammation and fibrosis, and myocardial injury were assessed. The expressions of pyroptosis-related proteins and nuclear factor-κB (NF-κB) pathway were evaluated.ResultsCrocin treatment could partially reverse the ICIs-related myocarditis in terms of improving heart function, ameliorating inflammation and fibrosis in the myocardium, and alleviating myocardial injury. Mechanistically, ICIs administration significantly activated pyrin domain-containing protein 3 (NLRP3) inflammasome in cardiomyocytes. Crocin treatments significantly downregulated the expression of NLRP3, cleaved gasdermin D (GSDMD), cleaved caspase1, interleukin-1β (IL-1β), and IL-18. Besides, crocin inhibited the activation of NF-κB pathway, which performed as reducing the phosphorylation of p-NF-kappa-B inhibitor-α (p-IκBα), degradation of IκBα, phosphorylation of p65 and p65 DNA binding activity both in vivo and in vitro.ConclusionBy reversing the pyroptosis in cardiomyocytes, crocin treatment in a mouse model exerted great potential to aid in the prevention of ICIs-related myocarditis from a novel target.

Immune checkpoint inhibitors-related myocarditis in patients with cancer: an analysis of international spontaneous reporting systems

BackgroundImmune checkpoint inhibitors-induced myocarditis presents unique clinical challenges. Here, we assessed post-marketing safety of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), programmed cell death-1 (PD-1), and programmed death-ligand 1 (PD-L1) inhibitors by mining the real-world data reported in two international pharmacovigilance databases.MethodsWe analyzed immune checkpoint inhibitors (ICIs)-associated fatal adverse drug events (ADEs) reports from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) collected from July 1, 2014 to December 31, 2019 and data from EudraVigilance (EV) database accessed on February 29, 2020. Three different data mining approaches were used to detect the signal of fatal myocarditis caused by ICIs.ResultsBased on 7613 ICIs-related ADEs reported to the EV database and 5786 ICIs-associated ADEs submitted to the FAERS database, the most frequently reported ADE was ipilimumab-related colitis. For myocarditis, nivolumab-associated myocarditis was the most common. Among the five fatal toxic effects associated with ICIs, the lethality rate of myocarditis was the highest. Therefore, we further analyzed ICI-associated myocarditis and found that elderly patients and male patients were more likely to develop ICIs-related myocarditis. The results of signal detection showed that the risk signal of avelumab-related myocarditis detected by reporting odds ratio (ROR) method and proportional reporting ratios (PRR) method was the highest, whereas the signal strength of ipilimumab-related myocarditis detected by Bayesian confidence propagation neural networks (BCPNN) method was the strongest.ConclusionThe findings of this study indicated the potential safety issues of developing myocarditis when using ICIs, which were consistent with the results of previous clinical trials and could provide a reference for clinical workers when using ICIs.

Risk factors for myocarditis associated with immune checkpoint inhibitors using real-world clinical data.

e15100 Background: Immune checkpoint inhibitors (ICIs) can cause unique, high-grade immune-related adverse events. Although rare, ICI related myocarditis has the highest fatality rate (~50%). Cardiovascular monitoring is not routinely performed in patients on ICI treatment, thus risk factors remain unknown. Characterizing rare but fatal cardiac toxicities requires integration of real-world data. Methods: U.S claims data (IBM MarketScan) of over 30 million commercially insured individuals was leveraged to identify 2,687,301 cancer patients between 2011-2018. Patients ≥18 years of age treated with ICIs (targeting CTLA4 (ipilimumab) and/or the PD1 (nivolumab, pembrolizumab)/PDL1 (atezolizumab, avelumab, durvalumab) alone or in combination with ICI and/or chemotherapy were identified and followed until disenrollment. Myocarditis, comorbidities, and treatment details were identified using diagnosis and billing codes. Analyses included descriptive statistics and Cox proportional hazards regression. Results: 16,541 ICI treated cancer patients were included (median age 60; 58% male). Myocarditis was identified in 252 (1.5%) patients, majority (90%) ≥50 years old (median 63) with 12,040 person-years of follow up. 62% received anti-PD1 monotherapy, 12% anti-CTLA4, and 15% received combination treatment with other ICIs and/or chemotherapy. Most common cancer types were lung (48%), melanoma (25%), and renal cancer (14%). Cumulative incidence of myocarditis at 1 year was 2.06%; 95% CI (1.78-2.37), median onset of 80.5 days, 42% occurring within 60 days of treatment. By univariate analyses, age, cancer type, diabetes (DM), hypertension (HTN), kidney, liver disease, atrial fibrillation (AF) were related to myocarditis. Risk was lower in patients who received anti-CTLA4 monotherapy (HR: 0.490; 95% CI: 0.26-0.92; p = 0.0251). On multivariable regression analyses only age, cancer type (renal, lung cancer), comorbidities DM and liver disease were significantly associated with myocarditis (Table). Conclusions: This is the largest real-world longitudinal study for ICI associated myocarditis showing higher than reported incidence and identifiable risk factors. [Table: see text]

PRESENTATION AND LONG TERM OUTCOMES OF IMMUNE CHECKPOINT INHIBITOR RELATED MYOCARDITIS

Cancer treatment in the past decade has rapidly changed with the introduction of immune checkpoint inhibitors (ICIs). Myocarditis is a rare but potentially deadly complication of ICI treatment. We aim to describe presentation and long-term outcomes of ICI related myocarditis in comparison to a

Impact of pericardial effusion for patients receiving immune checkpoint inhibitors.

e14121 Background: Various immune-related adverse events (IRAE) have been reported with the use of immune checkpoint inhibitors (ICI). Although a rare event, the increasing incidence of ICI related myocarditis and its reported high mortality raises concern. Cardiovascular IRAE such as pericardial effusions (PE) have been documented in case reports and case series but their clinical significance is unclear. Methods: Retrospective chart review was performed on 1075 patients receiving ICI between 2015 and 2017 with baseline echocardiograms without pericardial effusions and follow up echocardiograms at MD Anderson Cancer Center. We collected baseline characteristics, laboratory findings, echocardiograms, and dates of ICI initiation, PE development, last follow up and death. Overall survival (time from first ICI therapy to death or last follow up) was calculated. Univariate Fine-Gray regression analyses were conducted to identify variables associated with PE to account for death as a competing risk event. A p-value of less than 0.05 indicated statistical significance. Results: After initiation of ICI, 78 patients (7.3%) developed PE of which 45 patients died (58%) compared to 347 deaths (35%) out of the 997 patients without PE. The median follow-up time was 445 days. Univariate Fine-Gray analyses predicting PE demonstrated lower body surface area, lowest nadir in left ventricular ejection fraction (LVEF), higher troponin levels, lower platelet counts, absence of ectopy and hyperlipidemia, and lack of avelumab in therapy as well as a history of heart failure with preserved or reduced ejection fraction, hematologic cancer, and peripheral artery stents were significantly associated with higher incidence of PE. Conclusions: While the development of PE is an IRAE or progression of cancer itself cannot be determined, this study indicates patients receiving ICI who developed PE had higher mortality. Those with greater troponin levels and substantial decline in LVEF were shown to have a greater propensity of developing PE, suggesting the possibility of an underlying myopericarditis. If PE develops during ICI therapy, providers should consider an expedited workup and treatment of ICI related myocarditis.