Molecular predictors and mechanisms of immune checkpoint inhibitor-induced myocarditis: A case-control study with translational correlates.
Authors: Steph A. Pang, Manuel Flores Molina, Pamela Thébault, Yuming Zheng, Hsiang Chou, Christophe Goncalves, Jingtao Wang, Sabin Dragos Filimon, Paulo Ricardo Santos Nunes Filho, Mariana Pilon Capella, Khashayar Esfahani, Caroline Maude Michel, Jun Ding, Sonia Victoria Del Rincon, Marie Hudson, Réjean Lapointe, Wilson H. Miller
Journal: Journal of Clinical Oncology (2024)

12031 Background: Myocarditis from immune checkpoint inhibition (ICI) has been reported in 0.04-1.14% of patients on ICI, with mortality up to 50%. Self-antigens driving ICI-myocarditis are largely unknown. Shared T cell clones between heart and tumor have not yet been identified. We present the Montreal Immune-Related Adverse Events (MIRAE) myocarditis project, which seeks to elucidate cellular and molecular drivers of ICI-myocarditis. Methods: Our case-control study comprises 3 groups of patients on ICI: 1) ICI-myocarditis (per ASCO diagnostic criteria); 2) non-ICI troponemia (elevated troponins from non-immune etiology); and 3) controls matched by tumor type, sex, and age, with no troponemia. We analyzed blood from prior to ICI, at time of troponemia, or at 3-6 months after ICI initiation. Our multiomics pipeline spans cytokine profiling, immune cell subpopulation profiling of peripheral blood mononuclear cells (PBMCs) via single cell RNA and T/B cell receptor sequencing, spatial single-cell imaging proteomics, and spatial transcriptomics to localize sources of upregulated cytokines and to visualize cell-cell interactions. Results: Of 560 patients treated with ICI in our biobank, 4.3% had ICI-myocarditis. 19 myocarditis stored samples were included in our study. All 19 patients received steroids. Additional treatments were mycophenolate (32%), tofacitinib (21%), plasmapheresis (21%), IVIG (21%) and alemtuzumab (5%). 5 patients (26%) developed arrhythmias. 10 (47%) had concurrent irAE. There were no major cardiac adverse events nor deaths from myocarditis or other irAE. These encouraging results may reflect our hospital protocol of troponin screening during first 3 cycles of ICI, leading to earlier diagnosis and treatment. Elevations of blood neutrophil-to-lymphocyte ratio, alanine transaminase, and aspartate aminotransferase were associated with ICI-myocarditis. Plasma cytokine profiling of 13 ICI-myocarditis cases and controls revealed significant elevations of IP10, IL10, IL15 and IL13 at time of myocarditis. Subpopulation profiling of PBMCs is ongoing. Spatial phenotyping of an ICI-myocarditis biopsy demonstrated T cell and macrophage infiltration among cardiocytes and granulocyte accumulation within fibrotic tissue. Spatial transcriptomics analysis is ongoing for the ICI-myocarditis biopsy and 2 controls. Conclusions: This is one of the largest translational studies of ICI-myocarditis and controls. Our patients had improved clinical outcomes compared to those reported in the literature, which may be a result from our early screening. Our multiomics analyses of their biospecimens contributes novel data, such as spatial proteomics and transcriptomics analyses on heart tissue. Advancing our understanding of ICI-myocarditis will allow us to design screening strategies and more targeted treatments for ICI-myocarditis.