Risk Factors for Immune Checkpoint Inhibitor-Mediated Cardiovascular Toxicities

Abstract

Purpose of review: Immune checkpoint inhibitors (ICIs) have improved the field of cancer, especially in patients with advanced malignancies. Nevertheless, cardiovascular immune-related adverse events (irAEs) with high mortality and morbidity have been observed, including myocarditis, pericarditis, and vasculitis. To date, only a few clinical risk factors have been described and are currently being investigated.

Recent findings: In this review, we address the four most prevailing risk factors for cardiovascular irAEs. ICI combination therapy is a predominant risk factor for developing ICI-mediated myocarditis. Additionally, ICI combined with other anti-cancer treatments (e.g., tyrosine kinase inhibitors, radiation, chemotherapy) seems to increase the risk of developing cardiovascular irAEs. Other risk factors include female sex, pre-existing cardiovascular disease, and specific tumors, on which we will further elaborate in this review. An a priori risk strategy to determine who is at risk to develop these cardiovascular irAEs is needed. Insights into the impact of risk factors are therefore warranted to help clinicians improve care and disease management in these patients.

Keywords: ICI; Myocarditis; Pericarditis; Risk factors; Vasculitis.

Fig. 1

ICI mechanisms of action. A CTLA-4, PD-1, and LAG-3 binding leads to T cell inhibition. B Immune checkpoint inhibitors (ICI) block T cell inhibition, allowing for T cell activation in the tumor microenvironment (incl. cytokine release) and a potent anti-tumor response. C It is hypothesized that cardiovascular immune-related adverse events (irAEs) could occur through direct interaction between T cells and cardiac cells. Created with Biorender. CTLA-4, Cytotoxic T-lymphocyte-associated protein 4; PD-1, programmed cell death protein-1; PD-L1/L2, programmed cell death protein-1-ligand 1/2; LAG-3, lymphocyte activation gene-3; MHC-II, major histocompatibility complex II

Fig. 2

A schematic overview of risk factors for ICI-mediated myocarditis. A ICI in combination with ICI or other cancer treatment is associated with higher incidence of ICI-mediated myocarditis. B Melanoma is the most common cancer in patients with ICI-mediated myocarditis. C Pre-existing cardiovascular disease (CVD) has been reported in the majority of people with ICI-mediated myocarditis, with most incidence in patients with heart failure and acute coronary syndrome (ACS). D ICI-mediated myocarditis has a higher incidence in females. CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-1, programmed cell death protein-1; PD-L1, programmed cell death protein-1-ligand 1; LAG-3, lymphocyte activation gene-3; TIK, tyrosine kinase inhibitor; ChemoTx, chemotherapy; RadioTx, radiotherapy. Data derived from [, , ••, , –41, 61]

Fig. 3

Potential risk factors for ICI-mediated myocarditis, pericarditis and vasculitis. Treatment regimen has been associated with the most cases of cardiovascular irAEs. Combination therapy seems specific for myocarditis, whereas anti-PD-1/PD-L1 mono-treatment seems most harmful in all three injuries. The female sex is implied to be a risk factor, most likely due to the autoimmune nature of cardiovascular irAEs. There also appears to be a trend in which cardiovascular irAE develops depending on the underlying cancer type. Furthermore, pre-existing CVD is indicated in the majority of patients with cardiovascular irAEs, specifically acute coronary syndrome (ACS) and heart failure. Created with Biorender