Cardiotoxicity of immune checkpoint inhibitors

Abstract

Cardiac toxicity after conventional antineoplastic drugs (eg, anthracyclines) has historically been a relevant issue. In addition, targeted therapies and biological molecules can also induce cardiotoxicity. Immune checkpoint inhibitors are a novel class of anticancer drugs, distinct from targeted or tumour type-specific therapies. Cancer immunotherapy with immune checkpoint blockers (ie, monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1) and its ligand (PD-L1)) has revolutionised the management of a wide variety of malignancies endowed with poor prognosis. These inhibitors unleash antitumour immunity, mediate cancer regression and improve the survival in a percentage of patients with different types of malignancies, but can also produce a wide spectrum of immune-related adverse events. Interestingly, PD-1 and PD-L1 are expressed in rodent and human cardiomyocytes, and early animal studies have demonstrated that CTLA-4 and PD-1 deletion can cause autoimmune myocarditis. Cardiac toxicity has largely been underestimated in recent reviews of toxicity of checkpoint inhibitors, but during the last years several cases of myocarditis and fatal heart failure have been reported in patients treated with checkpoint inhibitors alone and in combination. Here we describe the mechanisms of the most prominent checkpoint inhibitors, specifically ipilimumab (anti-CTLA-4, the godfather of checkpoint inhibitors) patient and monoclonal antibodies targeting PD-1 (eg, nivolumab, pembrolizumab) and PD-L1 (eg, atezolizumab). We also discuss what is known and what needs to be done about cardiotoxicity of checkpoint inhibitors in patients with cancer. Severe cardiovascular effects associated with checkpoint blockade introduce important issues for oncologists, cardiologists and immunologists.

Trastuzumab-mediated cardiotoxicity: current understanding, challenges, and frontiers

“…Several monoclonal antibodies targeted against immune checkpoints gained Food and Drug Administration (FDA) approval in recent years including anti-CTLA-4 antibodies (ipilimumab and tremelimumab), anti-PD-1 antibodies (nivolumab and pembrolizumab), and anti-PDL1 antibodies (atezolizumab, avelumab, and durvalumab) [30]. Although, immune checkpoint inhibitors have revolutionized the clinical management of advanced staged malignancies with dismal prognosis [31], activation of immune system by these therapeutic monoclonal antibodies also causes wide spectrum of adverse events, including myocarditis, myocardial fibrosis, cardiomyopathy, and heart failure; mechanisms of which are not yet identified. Recently, Johnson et al .…”

Sex Differences in Tolerability to Anti-Programmed Cell Death Protein 1 Therapy in Patients with Metastatic Melanoma and Non-Small Cell Lung Cancer: Are We All Equal?

“…These adverse events are believed to emerge from immunologic hyper‐activation of normal tissues and are usually treated with immunosuppressive agents such as corticosteroids or tumor necrosis factor‐alpha antagonists . Although rare, fulminant and even fatal toxicities may occur with immune checkpoint inhibitors , and therefore, prompt recognition, identification of possible risk factors, and early treatment are vital.…”

Nivolumab-induced Myocarditis Successfully Treated with Corticosteroid Therapy: A Case Report and Review of the Literature

“…From previous reports, the characteristic histological finding of nivolumab-induced myocarditis is T-cell inflammation. Four potential mechanisms of ir-AE have been proposed (17). First, ICIs (monoclonal antibodies) binding directly to cell surface proteins, such as cytotoxic T lymphocyte antigen 4 (CTLA4), which is expressed on normal tissues, can cause T-cell infiltration and injury to tissues due to complement mediation.…”