The Evolving Immunotherapy Landscape and the Epidemiology, Diagnosis, and Management of Cardiotoxicity: JACC: CardioOncology Primer

Abstract

Immune checkpoint inhibitors (ICIs) are newer therapies being applied to an increasing number of patients with cancer. Data suggest that up to 36% of cancer patients may be eligible for immunotherapy and, in late 2019, there were more than 3,362 clinical trials initiated to evaluate the effectiveness of immunotherapy, either as single agents or in combination with other immunotherapy, targeted therapies, or traditional cytotoxic or radiation therapy. With the combination of both immune and non-immune treatment approaches, the complexity in making the diagnosis of cardiotoxicity related to an ICI will increase substantially. Here, we summarize the published data on the epidemiology, diagnosis, and management of cardiotoxicity of ICIs. This is a rapidly evolving field, and as our understanding continues to evolve, previously considered hypotheses may not prove to be entirely correct. Research and continued collaborations are urgently needed to provide evidence-based cardiovascular care for this rapidly expanding and vulnerable cohort of patients. (J Am Coll Cardiol CardioOnc 2021;3:35-47) © 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords: diagnosis; epidemiology; immunotherapy; myocarditis; treatment.

Graphical abstract

Figure 1

Mechanisms of Action of Immune Checkpoint Inhibitors (A) Cancer cells escape immune recognition by triggering the overexpression or activation of inhibitor checkpoint pathways (e.g., PD-1 and PD-L1 or CTLA-4) that suppress the host’s ability to mount an immune response against the tumor. (B) Immune checkpoint inhibitors are monoclonal antibodies (e.g. anti-PD-1, anti-PD-L1 and anti-CTLA-4) that block this process, thus activating T cells and initiating an adaptive immune response, allowing the immune system to recognize abnormal cancerous cells. CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; MHC = major histocompatibility complex; PD-1 = programmed death receptor 1; PD-L1 = programmed death receptor 1 ligand; TCR = T cell receptor.

Figure 2

Proposed Diagnostic Algorithm for Immune Checkpoint Inhibitor-Associated Myocarditis We propose the following diagnostic algorithm. The arrows represent steps forward in the diagnosis. An electrocardiogram (ECG), troponin, B-type natriuretic peptide (BNP), and echocardiogram including global longitudinal strain (GLS) should be obtained as the initial tests. Unstable patients should undergo cardiac catheterization. Stable patients should rule out acute coronary syndrome (ACS) and obtain cardiac magnetic resonance (CMR) imaging with parametric mapping. If patients with persistent clinical suspicion despite a normal CMR, endomyocardial biopsy (EMB) is recommended to confirm the diagnosis. CV = cardiovascular; ICI = immune checkpoint inhibitor.

Figure 3

Proposed Treatment Algorithm for Immune Checkpoint Inhibitor-Associated Myocarditis We propose the following treatment algorithm based on our experience. The arrows represent steps forward in the treatment. Immune checkpoint inhibitors (ICI) should be discontinued and high-dose corticosteroids (i.e., methylprednisolone 1,000 mg/day) should be initiated in patients with ICI-associated myocarditis. Based on patients’ clinical presentations and responsiveness to the initial therapy, different therapeutic approaches can be considered. There are no high-level data supporting the proposed treatment approach. ATG = antithymocyte globulin; IVIG = intravenous immunoglobulin; other abbreviations as in Figures 1 and 2.

Central Illustration

Immune Checkpoint Inhibitors Leading to Cardiotoxicities and Major Adverse Cardiovascular Events Immune checkpoint inhibitors can lead to cardiovascular toxicities, which include myocarditis and pericarditis. Although there are no robust clinical data to support whether immune checkpoint inhibitors (ICIs) accelerate atherosclerosis, there is significant scientific plausibility to support the hypothesis that ICI use increases atherosclerosis. The public health impact of defining the association between ICI and atherosclerosis is significant. Patients with new cardiac signs or symptoms should undergo thorough cardiovascular assessments to evaluate the occurrence of cardiovascular outcomes. ECG = electrocardiogram; GLS = global longitudinal strain.