Immune Checkpoint Inhibitor Associated Myocarditis and Cardiomyopathy: A Translational Review

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized oncology and transformed the treatment of various malignancies. By unleashing the natural immunological brake of the immune system, ICIs were initially considered an effective, gentle therapy with few side effects. However, accumulated clinical knowledge reveals that ICIs are associated with inflammation and tissue damage in multiple organs, leading to immune-related adverse effects (irAEs). Most irAEs involve the skin and gastrointestinal tract; however, cardiovascular involvement is associated with very high mortality rates, and its underlying pathomechanisms are poorly understood. Ranging from acute myocarditis to chronic cardiomyopathies, ICI-induced cardiotoxicity can present in various forms and entities. Revealing the inciting factors, understanding the pathogenesis, and identifying effective treatment strategies are needed to improve the care of tumor patients and our understanding of the immune and cardiovascular systems.

Immune checkpoint inhibitors associated cardiovascular immune-related adverse events

“…Notably, the blockade of the CTLA-4 and PD-1/PD-L1 pathways is significantly associated with the occurrence and progression of both myocarditis and atherosclerosis ( 42 , 138 , 146 , 148 , 151 – 155 , 178 – 181 , 191 – 193 , 195 – 198 , 282 ). While combining ICIs had significantly improved therapeutic effectiveness, it also carries a considerably higher risk of cardiac irAEs, resulting in increased incidence and mortality rates compared to single-agent therapy ( 5 , 15 , 117 , 121 , 122 ).…”

“…While the incidence of cardiovascular adverse events caused by ICIs is relatively low, the associated mortality rate is alarmingly high (111). The spotlight on cardiac irAEs began in 2016, with Johnson et al documenting two instances of fatal myocarditis occurring after ICI treatment (121,122). Subsequently, the spectrum of cardiovascular irAEs has expanded to include conditions such as myocardial infarction, atrioventricular (AV) block, various forms of arrhythmias (including supraventricular and ventricular), sudden cardiac death, Tako-Tsubo cardiomyopathy, non-inflammatory cardiomyopathy, pericarditis, pericardial effusion, ischemic stroke, venous thromboembolism and accelerated atherosclerosis (123).…”

“…Notably, the initial trials of ICIs did not include proactive screenings for myocarditis, which raises concerns that some cases may have gone undetected ( 139 ). It was reported that approximately 0.04% to 1.14% of cases involving ICI treatments are linked to myocarditis ( 18 , 121 ). Myocarditis stands out as the most frequently reported cardiac irAE, primarily due to its significant morbidity rates ( 13 , 16 , 140 ).…”

“…A risk factor for myocarditis associated with ICIs is the utilization of combined ICI therapy ( 121 ). For instance, the combined usage of nivolumab (anti-PD-1 mAb) and ipilimumab (anti-CTLA-4 mAb) leads to a 4.74-fold increase in the risk of myocarditis when contrasted with the utilization of nivolumab (anti-PD-1 mAb) as a standalone therapy ( 122 ).…”

Cellular therapeutics and immunotherapies in wound healing – on the pulse of time?

“…Since 2011, there have been 11 immune checkpoint inhibitors approved by the FDA (as of June 2023), all of which are monoclonal antibodies indicated for the treatment of malignancies [ 94 , 109 ]. The immune checkpoints targeted by these approved checkpoint inhibitors include cytotoxic T-lymphocyte antigen-4, programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and lymphocyte activation gene 3 [ 94 , 109 ]. There have not yet been any checkpoint inhibitors approved specifically for wound healing indications.…”