Cardiotoxicity associated with immune checkpoint inhibitor therapy: a meta‐analysis

Abstract

This study aimed to estimate the incidence of cardiac immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors (ICIs).

A Systematic Review of the Mechanisms Involved in Immune Checkpoint Inhibitors Cardiotoxicity and Challenges to Improve Clinical Safety

“…The hazard ratio can be increased even in monotherapies for malignant melanoma (HR = 4.3 for anti-PD-1 and 4.93 for anti-CTLA-4) ( Totzeck et al, 2021 ). Among cardiac irAEs, as previously reported by a systematic PubMed review, myocarditis is the most frequent (51%) of cardiac irAEs, representing 0.72% of total irAEs, with an increased rate in dual ICI therapies (two-fold increased rate) ( Rubio‐Infante et al, 2021 ). In VigiBase, WHO’s global international pharmacovigilance database, ICI-induced myocarditis ranged from 0.54% for monotherapy to 1.22% for patients treated with combination therapy with a two-fold increased rate ( Wei et al, 2021 ).…”

“…Striational antibodies might form an immune complex and CDC ( Picardo et al, 2019 ). Finally, autoantibodies can directly recognize their antigen on the cardiomyocyte’s surface, induce ADCC ( Haanen and Robert, 2015 ), or promote an agonist/antagonist response ( Rubio‐Infante et al, 2021 ). AChR: acetylcholine receptor; ADCC: antibody-dependent cellular cytotoxicity; APC: antigen-presenting cell; C1q: complement component 1q; CD: Cluster of differentiationCD4+: T helper cell; CD8+: T cytotoxic cell; CDC: complement-dependent cytotoxicity; CTLA-4: cytotoxic T-lymphocyte-associated antigen 4; FcγR: Fc gamma receptors; Kv1.4: potassium voltage-gated channel; M2: muscarinic acetylcholine receptor 2; PD-1: programmed death 1; PD-L1: programmed death-ligand 1; RyR: ryanodine receptor.…”

“…Although cardiac irAEs reported in clinical trials after ICI treatments have a relatively low incidence, 3.1% in monotherapies and 5.8% in dual/combination (two different ICIs) therapies ( Rubio‐Infante et al, 2021 ), they can be life-threatening. The hazard ratio can be increased even in monotherapies for malignant melanoma (HR = 4.3 for anti-PD-1 and 4.93 for anti-CTLA-4) ( Totzeck et al, 2021 ).…”

“…Other cardiotoxicities have been described as irAEs, including pericarditis and myocardial infarction, albeit with a lower frequency (<1%) ( Pauken and Wherry, 2015 ). In a recent pharmacovigilance analysis, it was found that cardiac irAEs in the vigiAccess database were mainly associated with myocarditis ( Rubio‐Infante et al, 2021 ). Recently in a metanalysis of randomized clinical trials including 32,518 patients, the ICIs therapies were associated with an increased risk of six different cardiac irAEs including myocarditis, pericardial diseases, heart failure, dyslipidemia, myocardial infarction, and cerebral arterial ischemia with a higher risk for myocarditis development (Peto OR: 4.42, 95% CI: 1.56–12.50, p < 0.01) ( Dolladille et al, 2021 ).…”

Current State of Pediatric Cardio-Oncology: A Review

“…Cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and the programmed cell protein-1 (PD-1) pathways are the two most common targets utilized with ICI [ 42 ]. Both of these pathways are critical in T-cell regulation; thus, altering the pathway has autoimmune side effects that may affect every organ [ 43 ].…”