Immune checkpoint inhibitor-related myocarditis: current understanding and potential diagnostic and therapeutic strategies

Abstract

Introduction: Myocarditis associated with immune checkpoint inhibitors presents with an often-severe clinical phenotype with arrhythmias and concurrent myositis. This condition tends to occur early after treatment onset and is associated with a high fatality rate. Diagnosis may be challenging, and treatment algorithms are still evolving.

Areas covered: This review will provide an overview of immune checkpoint inhibitor mechanism of action and how it relates to myocarditis pathophysiology, diagnostic algorithms and potential pitfalls, and emerging treatment approaches published until May 2023. We will focus on the state of the field and potential new directions in research and patient care. We will also provide consensus-based diagnostic and therapeutic algorithms endorsed by major societies.

Expert opinion: The field needs more evidence-based approaches to risk stratification so that therapy can be tailored toward less cardiotoxic alternatives in high-risk patients. For diagnostic and therapeutic approaches, data from animal models are unlikely to provide conclusive evidence given the complexity of the human immune system. We strongly invite practitioners in the field to contribute every case to the ongoing multicenter registries.

Keywords: ICI; Immune checkpoint inhibitors; cardiotoxicity; immune-related adverse events; immunotherapy; irAEs; myocarditis.

Figure 1.

Schematic of T-cell activation and exhaustion Naïve T-cells are primed through a two-signal process. The first signal requires antigen binding to the T-cell receptor (TCR) and the second signal is provided by the binding of activated antigen presenting cell (APC) ligands CD80 and 86 (also called B7–1 and B7–2) to CD28 on the T-cell. However, when the stimulation becomes chronic, the antigen-specific T-cells become exhausted and functionally unresponsive via upregulation of immune checkpoints CTLA-4 and PD-1. In the tumor tissue, cytotoxic T-cell function occurs when the TCR re-encounters the antigen for which it was primed. However, chronic stimulation induces expression of PD-1 on the exhausted T-cell. Many cancer cells express PD-L1. Engagement of PD-1 and PD-L1 results in suppression of the effector T-cell activity. Immune checkpoint inhibitors are monoclonal antibodies which attenuate these negative regulators of activation. Mφ: Macrophage; MHC: Major histocompatibility complex; _exTcell: Exhausted T-cell; Ca: Cancer cell.

Figure 2.

Diagnostic Criteria for ICI Myocarditis Adapted from Lyon AR, López-Fernández T, Couch LS, et al. 2022 ESC Guidelines on cardio-oncology [48]