New immunomodulators known as "immune checkpoint inhibitors" are being increasingly used for the treatment of common malignancies such as metastatic melanoma, non-small cell lung cancer, and renal cell carcinoma. These monoclonal antibodies interact with specific costimulatory or co-inhibitory molecules expressed on the surface of activated T cells. As such, they take advantage of the regulatory mechanisms that govern T cell activation to strengthen the immune response against cancer cells and minimize tumor evasion from host immunity. To date, development of these agents has focused on two major targets: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the programmed cell death protein-1 (PD-1) pathway.

CTLA-4 is an important regulator of the early phase of T cell activation.¹ Signaling through CTLA-4 counteracts CD28-mediated costimulation and induces an inhibitory program that stops T cell proliferation. Anti-CTLA-4 antibodies thus prevent inhibitory signaling to effector T cells, thereby increasing the ratio of effector cells to regulatory cells and augmenting the antitumor immune response.² Ipilimumab is a first-in-class anti-CTLA4 human monoclonal antibody approved for the treatment of metastatic melanoma based on two large clinical trials demonstrating a marked improvement in overall survival.^3,4 A second anti-CTLA-4 antibody, tremelimumab, is currently under investigation.

In contrast to CTLA-4, signaling through the PD-1 pathway occurs primarily during the late phase of T cell activation.¹ PD-1 binds to PD-L1 (programmed death ligand-1) and PD-L2 (programmed death ligand-2) on antigen-presenting cells to induce anergy in effector T cells. Pembrolizumab and nivolumab are human monoclonal antibodies that block ligand binding to PD-1, leading to T cell activation. Both pembrolizumab and nivolumab significantly improved overall survival in the setting of melanoma^5,6 and have been FDA-approved for use in patients who progress on treatment with ipilimumab. Nivolumab is also approved for patients whose tumors express the BRAF V600 mutation.⁷ Moreover, PD-1 blockade may be particularly beneficial when combined with anti-CTLA4 therapy in specific patient populations.⁸ In addition to its use in melanoma, recent randomized clinical trials have demonstrated an increase in overall survival with nivolumab compared with standard therapies for advanced non-small cell lung cancer⁹ and renal cell carcinoma.¹⁰ Newer anti-PD-1 antibodies, such as pidilizumab, as well as several anti-PD-L1 antibodies are currently under study.

Given the impressive impact on cancer outcomes observed with immune checkpoint blockade, its use as a therapeutic strategy in cancer patients has grown rapidly within the past few years. Immune checkpoint inhibitors are generally well-tolerated compared with conventional cytotoxic chemotherapies, although a number of potentially serious immune-related adverse events have been reported involving the gastrointestinal system, skin, endocrine system, liver, and lung.¹¹ Cardiovascular (CV) toxicity has been reported infrequently but can lead to significant morbidity and mortality, as highlighted by the following preclinical and clinical reports.

Data from animal models suggest that modulation of the PD-1 pathway can lead to immune-mediated CV toxicity, primarily in the form of autoimmune myocarditis. Knockout of the PD-1 receptor in mice causes severe dilated cardiomyopathy characterized by high levels of immunoglobulin G autoantibodies that react specifically to cardiac troponin I.^12,13 In mouse models of lupus and other experimentally induced inflammatory states, inhibition of the PD-1 pathway has been recognized as an essential mediator of autoimmune myocarditis^14-16 and is similarly associated with high-titer autoantibodies against cardiac myosin.¹⁶

Though rare, immune-mediated cardiac toxicity has been observed in patients enrolled in large clinical trials and in individual case reports. In accordance with preclinical data, autoimmune myocarditis has been reported with both anti-CTLA4 and anti-PD-1 therapies. In a randomized placebo-controlled trial of ipilimumab for high-risk melanoma, 1 patient of the 475 assigned to the treatment group died of myocarditis.¹⁷ Similarly, in a phase I trial, 1 patient of a total of 207 patients treated with anti-PD-L1 antibody was diagnosed with myocarditis.¹⁸ A recent case report described a 73-year-old patient with metastatic melanoma treated with pembrolizumab who developed autoimmune myocarditis, resulting in severe left ventricular systolic dysfunction and congestive heart failure.¹⁹ Endomyocardial biopsy demonstrated lymphocytic infiltration with predominantly CD8-positive cells, findings that have been previously observed in tumor samples from patients treated with immune checkpoint inhibitors.²⁰ The patient was treated with corticosteroids and neurohormonal blockade, resulting in recovery of left ventricular function. However, the decision was made to abort immune checkpoint therapy, and no other antitumor therapy was initiated in this case.

Other cardiac toxicities have been reported with the use of immune checkpoint inhibitors, particularly with anti-CTLA-4 therapy. One patient treated with ipilimumab developed Takotsubo cardiomyopathy (apical ballooning syndrome), and no other precipitating stressor was identified.²¹ Another patient treated with ipilimumab developed pericarditis and pericardial effusion with tamponade physiology.²² Analysis of the pericardial fluid demonstrated 90% lymphocyte predominance. Pericardial tissue was subsequently obtained during a pericardial window procedure, and pathology demonstrated acute fibrinous pericarditis with no evidence of malignancy or microorganisms. The patient also developed hypothyroidism and adrenal insufficiency related to immune checkpoint therapy, and high-dose corticosteroids were initiated with good response. Of note, this patient presented with pericardial involvement 2 weeks after his last exposure to ipilimumab, suggesting that CV immune-related adverse events may occur even after immune checkpoint inhibition has been discontinued. At present, there are no specific guidelines for echocardiographic monitoring or management of CV toxicities included in the package inserts for ipilimumab, pembrolizumab, or nivolumab.

In summary, immune checkpoint inhibition has demonstrated superb efficacy in a variety of malignancies that have historically conferred a poor prognosis. Preclinical data support the importance of immune checkpoints in the heart and provide mechanistic insight into the clinical observations of autoimmune myocarditis, pericarditis, and other CV immune-related adverse events reported to date. The current experience with adverse CV events related to these agents is limited to a handful of patients in clinical trials as well as case reports. As novel immunotherapies come to market, awareness of cardiac toxicities will become increasingly important as the indications for immune checkpoint inhibitors continue to expand. Future studies will be necessary to identify patients at risk for the development of cardiac immune-related adverse events and to determine optimal management strategies.

References

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Keywords: Adrenal Cortex Hormones, Adrenal Insufficiency, Antibodies, Monoclonal, Antigen-Presenting Cells, B7-H1 Antigen, Apoptosis Regulatory Proteins, Autoantibodies, Biopsy, CTLA-4 Antigen, Carcinoma, Non-Small-Cell Lung, Carcinoma, Renal Cell, Cardiac Myosins, Cardiomyopathy, Dilated, Cardiotoxicity, Cell Proliferation, Endocrine System, Heart Failure, Hypothyroidism, Immunoglobulin G, Immunologic Factors, Immunotherapy, Melanoma, Mutation, Myocarditis, Pericardial Effusion, Pericarditis, Prognosis, Programmed Cell Death 1 Receptor, T-Lymphocytes, Cytotoxic, Takotsubo Cardiomyopathy, Troponin I, Ventricular Function, Left

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