Cardiac Toxicity Associated with Immune Checkpoint Inhibitors: A Systematic Review

Abstract

Immune checkpoint inhibitors (ICIs) are an important advancement in the field of cancer treatment, significantly improving the survival of patients with a series of advanced malignancies, like melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and Hodgkin lymphoma. ICIs act upon T lymphocytes and antigen-presenting cells, targeting programmed cell death protein 1 (PD1), programmed cell death protein ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), breaking the immune tolerance of the T cells against malignant cells and enhancing the body’s own immune response. A variety of cardiac-adverse effects are associated with ICI-based treatment, including pericarditis, arrhythmias, cardiomyopathy, and acute coronary syndrome, with myocarditis being the most studied due to its often-unexpected onset and severity. Overall, Myocarditis is rare but presents an immune-related adverse event (irAE) that has a high fatality rate. Considering the rising number of oncological patients treated with ICIs and the severity of their potential adverse effects, a good understanding and continuous investigation of cardiac irAEs is of the utmost importance. This systematic review aimed to revise recent publications (between 2016–2022) on ICI-induced cardiac toxicities and highlight the therapeutical approach and evolution in the selected cases.

Cardiotoxicity, Cardioprotection, and Prognosis in Survivors of Anticancer Treatment Undergoing Cardiac Surgery: Unmet Needs

“…ICIs act upon T lymphocytes and antigen-presenting cells, versus programmed cell death protein 1 (PD1), programmed cell death protein ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), deleting the immune tolerance of the T cells against cancer cells [ 46 ]. ICIs may be associated with pericarditis, arrhythmias, cardiomyopathy, and acute coronary syndrome; in particular, myocarditis has been found in 0.1% of the patients taking nivolumab as monotherapy, and 0.3% in those treated with nivolumab and ipilimumab [ 47 ], with a reported mortality rate in systematic reviews as high as 50% [ 48 ]. Recently, pembrolizumab (anti PD-1) used in 30 patients affected by classic and endemic Kaposi’s sarcoma showed effective anti-tumor activity with an acceptable safety profile, as cardiac treatment-related adverse events occurred in 6% (acute HF) and discontinuation was required in two (12%, due to acute reversible HF) [ 49 ].…”

Cardiovascular Adverse Events and Immune-related Adverse Events Associated with PD-1/PD-L1 Inhibitors for Head and Neck Squamous Cell Carcinoma (HNSCC): A Real-world study (RWS) by Bayesian Disproportional Analysis Based on the FDA Adverse Event Reporting System (FAERS)

“…Prolonged exposure to PD-L1 leads to T cell exhaustion, thereby inhibiting the host's immune response to tumors and facilitating immune escape [45][46][47][48]. PD-1/PD-L1 inhibitors work by blocking this pathway, allowing T cells to survive, proliferate, and enhance their killing ability, thus achieving an anti-tumor effect [49]. However, PD-L1 is not only present in target tumor cells but is also widespread in solid organ cells such as the lungs, pancreas, gastrointestinal tract, tonsils, placenta, liver, and heart [50,51].…”

Risk Factors for Immune Checkpoint Inhibitor–Mediated Cardiovascular Toxicities

“…Additionally, ICI-mediated pericardial disease was associated with a 1.5-fold mortality risk. In a recent systematic review of case studies, anti-PD-1 therapy was used in all patients that presented with ICI-mediated pericarditis [ 19 ]. As with myocarditis, pericarditis due to anti-PD-1 or anti-PD-L1 monotherapy occurred more frequently than with anti-CTLA-4 (0.36% and 0.16%, respectively) with a ROR of 2.28 [1.27–4.12] [ 5 ].…”