Abstract IA21: Immune Checkpoint Inhibitor-Associated Myocarditis: Learning from mice and humans

We and others have defined cardiovascular toxicities including myocarditis as an infrequent, but often fatal toxicity associated with immune checkpoint inhibitors (ICI).1 ICI-myocarditis is characterized by refractory electrophysiological disturbances, concomitant myositis, T-cell and macrophage infiltration into the myocardium and frequent mortality.2-4 Existing clinical practice extrapolates from general myocarditis literature for diagnosis of ICI-associated myocarditis with diagnosis being made using a combination of biomarkers (specifically troponin), cardiac imaging and biopsy.5 To better define mechanisms of ICI-associated myocarditis, our group has developed several mouse models. These include pharmacological models and genetic mouse models (where one or more immune checkpoints are genetically deleted). Specifically, monoallelic loss of Ctla4 (gene for CTLA-4) in the context of complete genetic absence of Pdcd1 (gene for PD-1) leads to premature death in approximately half of mice, resulting from myocardial infiltration by T cells and macrophages and severe electrocardiographic abnormalities, closely recapitulating the clinical and pathologic hallmarks of ICI-associated myocarditis observed in patients.6 Using this model, we show that Ctla4 and Pdcd1 functionally interact in a gene dosage–dependent manner, providing a mechanism by which myocarditis arises with increased frequency in the setting of combination ICI therapy. We demonstrate that intervention with CTLA4–Ig (abatacept) is sufficient to ameliorate disease progression and additionally provide a case series of patients in which abatacept mitigates the fulminant course of ICI myocarditis.7 More recently, we show that single cell RNA/T cell receptor (TCR) sequencing on the cardiac immune infiltrate of ICI-myocarditis mice identifies clonal effector CD8+ T cells as the dominant cell population. Treatment with anti-CD8, but not anti-CD4, depleting antibodies rescued survival myocarditis with adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients which required CD8+ T cells. Alpha-myosin, a cardiac specific protein absent from the thymus was identified as the cognate antigen source for three MHC-I restricted TCRs derived from mice with fulminant myocarditis. Peripheral blood T cells from three patients with ICI-myocarditis were expanded by alpha-myosin peptides, and these alpha-myosin expanded T cells shared TCR clonotypes with diseased heart and skeletal muscles, indicating that alpha-myosin may be a clinically important autoantigen in ICI-myocarditis. These studies underscore the critical role for cytotoxic CD8+ T cells, are the first to identify a candidate autoantigen in ICI-myocarditis and yield new insights into ICI toxicity pathogenesis. We have leveraged these mouse models and a growing population of ICI-myocarditis cases from around the world to define novel diagnostic and treatment strategies for these groups of patients.

Citation Format: Javid Moslehi. Immune Checkpoint Inhibitor-Associated Myocarditis: Learning from mice and humans [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr IA21.