Elsevier

The Lancet Oncology

Volume 19, Issue 9, September 2018, Pages e447-e458
The Lancet Oncology

Review
Immune checkpoint inhibitors and cardiovascular toxicity

https://doi.org/10.1016/S1470-2045(18)30457-1Get rights and content

Summary

Immune checkpoint inhibitors are a new class of anticancer therapies that amplify T-cell-mediated immune responses against cancer cells. Immune checkpoint inhibitors have shown important benefits in phase 3 trials, and several agents have been approved for specific malignancies. Although adverse events from immune checkpoint inhibitors are a common occurrence, cardiotoxic effects are uncommon, but are often serious complications with a relatively high mortality. Most cardiotoxic effects appear to be inflammatory in nature. Clinical assessment of a combination of biomarkers, electrocardiography, cardiac imaging, and endomyocardial biopsy can be used to confirm a possible diagnosis. In this Review, we discuss the epidemiology of immune checkpoint inhibitor-mediated cardiotoxic effects, as well as their clinical presentation, subtypes, risk factors, pathophysiology, and clinical management, including the introduction of a new surveillance strategy.

Introduction

A fundamental property of many cancers is the ability to avoid the host immune response and allow cell proliferation and metastasis. Harnessing the immune system to target cancer has been a strategy used in oncology for many decades.1 In the past 10 years, a major advancement has been the use of immune checkpoint inhibitors (ICIs) to block inhibitory receptors expressed on T lymphocytes, such as cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1),2, 3, 4, 5 or their corresponding ligands expressed on tumour cells, such as programmed cell death 1 ligand-1 (PD-L1).6, 7, 8, 9, 10, 11, 12 When these inhibitory T-cell receptors bind to these specific ligands on host cells, including cancer cells, receptor binding prevents T-cell activation and the resulting immune response. Thus, the expression of ligands such as PD-L1 is an important immune evasion mechanism by cancer cells to avoid a host immune response.

Therapeutically blocking inhibitory molecular axes using specific monoclonal antibodies (ie, ICIs) targeting CTLA-4 (ipilimumab), PD-1 (nivolumab or pembrolizumab), and PD-L1 (atezolizumab, avelumab, or durvalumab), either as a monotherapy or combination therapy, activates the immune system to recognise and target cancer cells via a T-cell-mediated immune response (appendix). The first clinical trials of immunotherapy have shown impressive results for advanced metastatic cancers, including melanoma, non-small-cell lung cancer (NSCLC), renal cell carcinoma, head and neck squamous cell carcinoma, urothelial cancer, refractory Hodgkin's lymphoma, and malignancies with microsatellite instability, and have led to fast-track approval of ICIs for several cancers by the US Food and Drug Administration (FDA) and the European Medicines Agency (table 1; appendix). In 2017, the US FDA granted accelerated approval for the use of pembrolizumab for mismatch repair-deficient tumours, marking the first tissue-agnostic and site-agnostic drug approval by the agency.13 Adjuvant immunotherapy has shown beneficial effects after surgery for melanoma,14 and after radical chemoradiation for NSCLC.15 Both the range of cancers for which ICIs are used and the complexity of treatment strategies that include ICIs in their treatment programme are increasing rapidly.16

Enhancement of immune responses by ICIs causes activation of T-cell responses systemically, producing a range of autoimmune toxicities, particularly with the use of two ICIs or a single ICI in combination with another cardiotoxic anticancer therapy (such as tyrosine kinase inhibitors). In the CheckMate 067 phase 3 trial of patients with metastatic melanoma,3 more than 90% of patients who received combined ipilimumab and nivolumab immunotherapy had at least one immune-related adverse event, and about 50% had a serious immune-related adverse event. The most common adverse events in patients receiving ICIs are fatigue, rashes, gastrointestinal side-effects (including diarrhoea and colitis), and increased liver transaminases. These effects are generally reversible and can be controlled with steroid therapy.

Emerging evidence shows immune responses in the cardiovascular system, particularly in the heart, for patients who are receiving ICI treatment.17 Although still relatively rare, the cardiovascular toxicity of immunotherapy is serious and potentially fatal, and the true incidence is unknown. This Review describes the latest evidence regarding the epidemiology of immune ICI-related cardiotoxic effects, as well as their clinical presentation and subtypes, its underlying mechanisms, and a possible framework for clinical management. Because prospective clinical studies on the cardiovascular complications of immunotherapy have not been done, the clinical management pathways discussed in this Review are the opinions of the authors based on currently available information.

Section snippets

Epidemiology of ICI-mediated cardiotoxicity

Evidence of cardiovascular toxicity secondary to immunotherapy initially emerged in single case reports presented at conferences and published by centres enrolling patients in phase 2 and 3 clinical trials of ICIs.18, 19, 20, 21 In 2016, Johnson and colleagues reported two cases of fatal fulminant myocarditis following combination ICI therapy, both occurring after the first dose of therapy.22 Further interrogation of immunotherapy trial data from Bristol-Myers Squibb—the manufacturer of

Clinical presentation of ICI-mediated cardiotoxic effects

Patients with ICI-mediated cardiotoxic effects can present to oncology, cardiology, acute medical, and community services. In general, myocarditis can prove to be challenging because of its diverse presentations. Several different forms of ICI-related cardiotoxicity have been reported from ICI clinical trials and current practice (figure).

ICI-related myocarditis can occur with acute heart failure, pulmonary oedema, and—in severe cases—cardiogenic shock, multiorgan failure, and ventricular

Mechanisms of ICI-mediated cardiotoxic effects

Preclinical studies support crucial roles for CTLA-4, PD-1, and PD-L1 signalling in cardiac–immune crosstalk, with abrogation of this pathway resulting in autoimmune myocarditis and cardiac failure.37, 38 T-cell-mediated responses to cardiac antigens also contribute to acquired disease progression and heart failure in preclinical models via an autoantibody-independent mechanism, with myocardial inflammatory cell infiltration and increasing myocardial fibrosis.39 Pd-1-knockout mice in a specific

Possible clinical management of cardiotoxic effects from ICIs

Management of acute cardiac complications of immunotherapy requires three complimentary approaches and depends on the severity of cardiotoxicity, ranging from asymptomatic laboratory abnormalities (eg, cardiac biomarker elevation or ECG changes) to fulminant myocarditis, cardiogenic shock, complete heart block, ventricular arrhythmias, and cardiac arrest. Diagnostic tests including cardiac biomarkers, ECG, and cardiac imaging are appropriate. If myocarditis is suspected, cardiac MRI with

Surveillance strategies for ICI-mediated cardiotoxic effects

An important clinical question is whether surveillance can detect early immunotherapy-mediated cardiotoxic effects before severe and life-threatening complications develop, as in surveillance for other cardiotoxic cancer therapies such as doxorubicin and trastuzumab. No evidence-based algorithm yet exists, and severe ICI-mediated cardiotoxic effects are still relatively rare in clinical practice, but the consequences are serious and frequently fatal. We propose a potential strategy for

Conclusion

ICIs are having a major impact on the direction of cancer treatment, providing long-term cancer-free survival in some patients with previously incurable disease, and are now licensed for various cancer types. ICI-mediated cardiotoxic effects are relatively rare, but when presented clinically can be serious and potentially fatal. Myocarditis, conduction disease with heart block, and ventricular arrhythmias are the most commonly reported toxic effects, but acute myocardial infarction,

Search strategy and selection criteria

We systematically reviewed PubMed and Ovid MEDLINE for published papers using the search terms “checkpoint inhibitor”, “CTLA-4”, “PD-1”, or “PD-L1” combined with “cardiotoxicity”, “myocarditis”, or “heart block”, without date restrictions. Food and Drug Administration labels were also included. The search was restricted to the English language.

References (58)

  • G Giaccone et al.

    Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study

    Lancet Oncol

    (2018)
  • AH Lichtman

    The heart of the matter: protection of the myocardium from T cells

    J Autoimmun

    (2013)
  • PL Lin et al.

    An increase in BAG-1 by PD-L1 confers resistance to tyrosine kinase inhibitor in non-small cell lung cancer via persistent activation of ERK signalling

    Eur J Cancer

    (2017)
  • GP Linette et al.

    Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma

    Blood

    (2013)
  • RD Anderson et al.

    Apical takotsubo syndrome in a patient with metastatic breast carcinoma on novel immunotherapy

    Int J Cardiol

    (2016)
  • S Du et al.

    PD-1 modulates radiation-induced cardiac toxicity through cytotoxic T lymphocytes

    J Thorac Oncol

    (2018)
  • R Bazaz et al.

    Mechanistic links between acute respiratory tract infections and acute coronary syndromes

    J Infect

    (2013)
  • J Larkin et al.

    Combined nivolumab and ipilimumab or monotherapy in untreated melanoma

    N Engl J Med

    (2015)
  • JD Wolchok et al.

    Overall survival with combined nivolumab and ipilimumab in advanced melanoma

    N Engl J Med

    (2017)
  • SM Ansell et al.

    PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma

    N Engl J Med

    (2015)
  • J Bellmunt et al.

    Pembrolizumab as second-line therapy for advanced urothelial carcinoma

    N Engl J Med

    (2017)
  • M Reck et al.

    Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer

    N Engl J Med

    (2016)
  • DT Le et al.

    Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

    Science

    (2017)
  • J Weber et al.

    Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma

    N Engl J Med

    (2017)
  • SJ Antonia et al.

    Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer

    N Engl J Med

    (2017)
  • MJ Flynn et al.

    Novel combination strategies for enhancing efficacy of immune checkpoint inhibitors in the treatment of metastatic solid malignancies

    Expert Opin Pharmacother

    (2017)
  • CJ Voskens et al.

    The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

    PLoS One

    (2013)
  • H Läubli et al.

    Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma

    J Immunother Cancer

    (2015)
  • S Yun et al.

    Late onset ipilimumab-induced pericarditis and pericardial effusion: a rare but life threatening complication

    Case Rep Oncol Med

    (2015)
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      Patients may present with symptoms of ACS or purely dyspnea, asthenia, fatigue. Echocardiography typically shows findings consistent with Takotsubo cardiomyopathy, although other causes such as ACS and myocarditis should be ruled out [30,48,49]. The pathophysiology of cardiotoxicity following ICI initiation is poorly understood and a critical area of further investigation both at the cellular and patient level.

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