Abstract IA10: Immune checkpoint inhibitor-associated cardiotoxicities: Learning from mice and humans
Authors: Moslehi Javid J. 
Published: March 2020

Abstract
Immune checkpoint inhibitors (ICI) have transformed cancer therapy, with regulatory approval now in 16 distinct cancer types. These agents include monoclonal antibodies blocking cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 receptor (PD-1), and its ligand (PD-L1), and work by activating the immune system (1). ICI can also lead to immune-related adverse events (irAE) including colitis, dermatitis, pneumonitis, endocrinopathies, and other irAE (2). Cardiovascular toxicities including myocarditis have emerged as uncommon but often fatal toxicities associated with ICI (3). Our group initially described cases of fulminant and fatal myocarditis after treatment with ICI (4). These patients presented with refractory electrophysiologic disturbances and concomitant myositis, with pathology confirming T-cell and macrophage infiltration into the myocardium (4). Since then other case series of myocarditis have described an estimated incidence of 0.3% to greater than 1% when ICI are used in combination (5-8). We published the largest such case series including 122 patients with ICI-associated myocarditis; these patients had early onset of symptoms (median 30 days after initial exposure to ICI), frequent deaths (50% mortality), and dramatically increased reporting of cases in 2017, the latter perhaps consistent with growing recognition of this new clinical syndrome as well as more widespread use of ICI (8). More recently, we have demonstrated association of ICI with other cardiovascular complications including myocarditis, pericarditis, vasculitis, and arrhythmias (8). 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 (9). We have recently developed case definitions for drug-induced myocarditis, especially in oncology clinical trials (10). To better define mechanisms of ICI-associated myocarditis, our group has developed several mouse models. These include pharmacologic models (where mice in various genetic backgrounds are treated with antibodies) and genetic mouse models (where one or more immune checkpoints are genetically deleted) and recapitulate the syndrome of myocarditis observed in humans treated with ICI. The mice have sudden cardiac death, electrocardiographic perturbations, and macrophage and T-cell infiltrations in the heart, all consistent with human disease (Moslehi et al., unpublished). Importantly, the early data suggest a critical role for CTLA-4 in the development of myocarditis. Treatment with abatacept attenuates the myocarditis in mice. We have extended these observations to humans where in at least one case, severe ICI-associated myocarditis was successfully treated with abatacept (11).
Citation Format: Javid J. Moslehi. Immune checkpoint inhibitor-associated cardiotoxicities: Learning from mice and humans [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA10.