Title:Immune Checkpoint Inhibitors and Cardiac Toxicity: An Emerging Issue
Volume: 25
Issue: 11
Author(s): Gilda Varricchi*, Giancarlo Marone, Valentina Mercurio, Maria Rosaria Galdiero, Domenico Bonaduce and Carlo G. Tocchetti*
Affiliation:
- Department of Translational Medical Sciences – Federico II University, Naples,Italy
- Department of Translational Medical Sciences – Federico II University, Naples,Italy
Keywords:
Cancer, cardiac toxicity, checkpoints, CTLA-4, melanoma, myocarditis, PD-1, PD-L1.
Abstract: Although survival of patients with different types of cancer has improved,
cardiotoxicity induced by anti-neoplastic drugs remains a critical issue. Cardiac dysfunction
after treatment with anthracyclines has historically been a major problem. However, also
targeted therapies and biological molecules can induce reversible and irreversible cardiac
dysfunction. Over the last years, cancer immunotherapies haverevolutionized the clinical
management of a wide spectrum of solid and hematopoietic malignancies previously endowed
with poor prognosis. Immune checkpoint inhibitors are at the forefront of immunotherapy: the
two most prominent are the targeting of cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-
4) and of programmed cell death 1 (PD-1) and its ligand PD-L1. Ipilimumab (anti-CTLA-4) is
the godfather of checkpoint inhibitors, whereas several blocking monoclonal antibodies
targeting PD-1 (nivolumab and pembrolizumab) and PD-L1 (atezolizumab, durvalumab,
avelumab, and BMS-946559) have been developed. Inhibitors of CTLA-4 and PD-1/PD-L1
pathway can unleash anti-tumor immunity and mediate cancer regressions. Although CTLA-4
inhibitors and PD-1 and PD-L1 blocking agents are frequently associated with a wide
spectrum of immune-related adverse events, cardiac toxicity has been underestimated.
However, early animal studies have demonstrated that after CTLA-4 inhibition and PD-1
deletion autoimmune myocarditis can occur. Moreover, PD-1 and PD-L1 can be expressed in
rodent and human cardiomyocytes. During the last years several cases of fatal heart failure
have been documented in melanoma patients treated with checkpoint inhibitors. The recent
experience with cardiovascular toxic effects associated with checkpoint inhibitors introduces
important concepts biologically and clinically relevant for future oncology trials and clinical
practice.
