Abstract B054: Immune checkpoint inhibitor-induced myocarditis and myocarditis-myositis overlap syndrome: identifying distinct molecular pathways for targeted therapeutic interventions

Abstract Background: Myocarditis from immune checkpoint inhibition (ICI) has been reported in 0.04-1.14% of patients on ICI, with mortality up to 50%. ICI-Myocarditis frequently overlaps with ICI-Myositis, and overlap is associated with increased mortality. Diagnosis and clinical management of concurrent myocarditis and myositis remains an unmet clinical challenge. We present the Montreal Immune-Related Adverse Events myocarditis project, which examines cellular and molecular drivers of ICI-myocarditis ± myositis. Methods: Our case-control study comprises 3 groups of patients on ICI: 1) ICI-myocarditis; 2) ICI-myocarditis-myositis overlap; and 3) controls without immune-related adverse events (irAEs) matched by tumor type, sex, and age. We analyzed blood prior to ICI, at time of myocarditis, and 3-6 months after ICI initiation. We developed a multiomics pipeline, spanning cytokine profiling on plasma using a 30-plex cytokine assay, multiplex proteomics analysis on plasma using the SomaScan 11K Assay, multiplexed single cell imaging technology, and spatial transcriptomics. Results: Of 560 patients treated with ICI in our biobank, 24 (4.3%) had ICI-myocarditis, of which 19 had samples that were included in this study. Nine of them had myocarditis-myositis. Five patients developed arrhythmias, but there were no major cardiac adverse events or deaths from myocarditis. Ten patients had concurrent irAE. All 19 patients were treated with steroids. Other treatments included mycophenolate (6 patients), tofacitinib (4 patients), plasmapheresis (4 patients), intravenous immunoglobulin (4 patients) and alemtuzumab (1 patient). Cytokine profiling of 13 ICI-myocarditis cases and controls demonstrated significant elevations of IP10, IL10, IL15 and IL13 at time of myocarditis. Multiplex proteomics assay demonstrated that ICI-myocarditis and ICI-myocarditis-myositis are phenotypically distinct, with higher levels of cardiomyocyte/skeletal myocyte-related proteins and IFN-gamma-induced proteins and increased interleukin-6-driven JAK-STAT3 signaling in ICI-myocarditis-myositis, compared to ICI-myocarditis. Additionally, patients who developed myocarditis with or without myositis had significantly decreased pre-ICI plasma levels of paired immunoglobin like type 2 receptor alpha (PILRA) compared to controls. Pathway analysis showed increased upregulation of genes known to contribute to hypertrophic cardiomyopathy, dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, in ICI-myocarditis/myositis compared to ICI-myocarditis alone. Spatial transcriptomics and mapping of infiltrating and tissue cells on biopsies of ICI-myocarditis, ICI-myositis and controls is ongoing. Conclusions: Our multiomics analyses of ICI-myocarditis revealed that the plasma proteome is significantly altered during myocarditis/myositis overlap, exhibiting stronger IFNg signatures and IL6 JAK STAT3 signaling, compared to ICI-myocarditis alone. Advancing our understanding of ICI-myocarditis ± myositis allows to design screening strategies, facilitate diagnosis and optimize treatment. Citation Format: Steph A. Pang, Manuel Flores Molina, Paméla Thébault, Yuming Zheng, Hsiang Chou, Christophe Goncalves, Jingtao Wang, Sabin Filimon, Paulo Nunes Filho, Mariana Pilon Capella, Khashayar Esfahani, Caroline M Michel, Jun Ding, Sonia V. Del Rincón, Marie Hudson, Réjean Lapointe, Wilson H Miller, Jr. Immune checkpoint inhibitor-induced myocarditis and myocarditis-myositis overlap syndrome: identifying distinct molecular pathways for targeted therapeutic interventions [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B054.