The Future of Cancer Treatments: Immunotherapies and Novel Pathways and Their CV Effects
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 melanoma5,6 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 myocarditis14-16 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.
- Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 2015;161:205-14.
- Quezada SA, Peggs KS, Curran MA, Allison JP. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest 2006;116:1935-45.
- Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-23.
- Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364:2517-26.
- Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015;372:2521-32.
- Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015;372:320-30.
- Weber JS, D'Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015;16:375-84.
- Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015;373:23-34.
- Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.N Engl J Med 2015;373:1627-39.
- Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803-13.
- Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review.Eur J Cancer 2016;54:139-48.
- Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 2001;291:319-22.
- Okazaki T, Tanaka Y, Nishio R, et al. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med 2003;9:1477-83.
- Lucas JA, Menke J, Rabacal WA, Schoen FJ, Sharpe AH, Kelley VR. Programmed death ligand 1 regulates a critical checkpoint for autoimmune myocarditis and pneumonitis in MRL mice. J Immunol 2008;181:2513-21.
- Tarrio ML, Grabie N, Bu DX, Sharpe AH, Lichtman AH. PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis. J Immunol 2012;188:4876-84.
- Wang J, Okazaki IM, Yoshida T, et al. PD-1 deficiency results in the development of fatal myocarditis in MRL mice. Int Immunol 2010;22:443-52.
- Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol 2015;16:522-30.
- Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455-65.
- Laubli H, Balmelli C, Bossard M, Pfister O, Glatz K, Zippelius A. Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma. J Immunother Cancer 2015;3:11.
- Ribas A, Comin-Anduix B, Economou JS, et al. Intratumoral immune cell infiltrates, FoxP3, and indoleamine 2,3-dioxygenase in patients with melanoma undergoing CTLA4 blockade. Clin Cancer Res 2009;15:390-9.
- Geisler BP, Raad RA, Esaian D, Sharon E, Schwartz DR. Apical ballooning and cardiomyopathy in a melanoma patient treated with ipilimumab: a case of takotsubo-like syndrome. J Immunother Cancer 2015;3:4.
- Yun S, Vincelette ND, Mansour I, Hariri D, Motamed S. Late onset ipilimumab-induced pericarditis and pericardial effusion: a rare but life threatening complication. Case Rep Oncol Med 2015;2015:794842.
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