Abstract B054: Immune checkpoint inhibitor-induced myocarditis and myocarditis-myositis overlap syndrome: identifying distinct molecular pathways for targeted therapeutic interventions
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".