Comparative immunologic characterization of autoimmune giant cell myocarditis with ipilimumab

Reuben, Alexandre; Macedo, Mariana Petaccia de; McQuade, Jennifer L.; Joon, Aron Y.; Ren, Zhiyong; Calderone, Tiffany L.; Conner, Brandy; Wani, Khalida; Cooper, Zachary A.; Tawbi, Hussein A.; Tetzlaff, Michael T.; Padera, Robert F.; Durand, Jean Bernard; Lazar, Alexander J.; Wargo, Jennifer A.; Davies, Michael A.

doi:10.1080/2162402x.2017.1361097

Cited by 50 publications

(54 citation statements)

References 20 publications

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“…4F). The increased expression of CXCR3 chemokine axis was also reported previously in the ICI-associated myocarditis heart tissues by others (15,43). Interestingly, CXCR3-CXCL9/CXCL10 and CCR5/CCL5 chemokine axes have also been shown to be particularly important in T-cell homing to tumors (44).…”

Section: Discussionsupporting

confidence: 73%

Myocarditis in Cynomolgus Monkeys Following Treatment with Immune Checkpoint Inhibitors

Roy

Golas

et al. 2019

Clinical Cancer Research

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Purpose: Immune checkpoint inhibitors (ICI) targeting PD1, PDL1, or CTLA4 are associated with immunerelated adverse events (irAE) in multiple organ systems including myocarditis. The pathogenesis and early diagnostic markers for ICI-induced myocarditis are poorly understood, and there is currently a lack of laboratory animal model to enhance our understanding. We aimed to develop such a model using cynomolgus monkeys. Experimental Design: Chinese-origin cynomolgus monkeys were dosed intravenously with vehicle or nivolumab 20 mg/kg plus ipilimumab 15 mg/kg once weekly and euthanized on day 29. Results: Multiple organ toxicities were observed in cynomolgus monkeys, and were characterized by loose feces, lymphadenopathy, and mononuclear cell infiltrations of varying severity in heart, colon, kidneys, liver, salivary glands, and endocrine organs. Increased proliferation of CD4 þ and CD8 þ T lymphocytes as well as an increase in activated T cells and central memory T cells in the blood, spleen, and lymph nodes, were observed. Transcriptomic analysis suggested increased migration and activation of T cells and increased phagocytosis and antigen presentation in the heart. Mononuclear cell infiltration in myocardium was comprised primarily of T cells, with lower numbers of macrophages and occasional B cells, and was associated with minimal cardiomyocyte degeneration as well as increases in cardiac troponin-I and NT-pro-BNP. Morphologically, cardiac lesions in our monkey model are similar to the reported ICI myocarditis in humans. Conclusions: We have developed a monkey model characterized by multiple organ toxicities including myocarditis. This model may provide insight into the immune mechanisms and facilitate biomarker identification for ICI-associated irAEs.

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Section: Discussionsupporting

confidence: 73%

Myocarditis in Cynomolgus Monkeys Following Treatment with Immune Checkpoint Inhibitors

Roy

Golas

et al. 2019

Clinical Cancer Research

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“…The first specific report of myocarditis during treatment with a PD‐1/PD‐L1 inhibitor was published in 2014 [27], and a number of cases of ICI‐associated myocarditis have been described since . In an early analysis of more than 20,000 patients treated with ICIs, either alone or in combination, the incidence of myocarditis was 0.09%; the incidence of fatal myocarditis in this sample was 0.03% .…”

Section: Current Knowledgementioning

confidence: 75%

Myocarditis Associated with Immune Checkpoint Inhibitors: An Expert Consensus on Data Gaps and a Call to Action

et al. 2018

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Immune checkpoint inhibitors are a class of drugs that trigger the immune system to recognize and fight cancer cells; however, related immune‐related adverse events are a challenge. This commentary describes a workshop convened by Project Data Sphere to determine best approaches in the treatment of myocarditis, with the goal of minimizing the risk of this adverse reaction in patients with cancer who are treated with immune checkpoint inhibitors.

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“…The exact mechanism of irAEs is not understood. Evolving data suggest that common high frequency T‐cell receptor sequences are found exist in cardiac muscle and tumor, raising the possibility of a shared antigen theory . Additionally, the relatively early onset of myocarditis after initiating ICI therapy and involvement of selective patients without a clear explanation supports hypotheses regarding the role of pre‐existing conditions that predispose to the development of myocarditis.…”

Section: Pathophysiologymentioning

confidence: 97%

Immune Checkpoint Inhibitor-Associated Myocarditis

2018

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Immune checkpoint inhibitors (ICIs) are approved for a wide range of malignancies. They work by priming the immune system response to cancer and have changed the landscape of available cancer treatments. As anticipated, modulation of the regulatory controls in the immune system with ICIs results in diverse immune-related adverse events, targeting any organ or gland. These toxicities are rarely fatal and generally regress after treatment discontinuation and/or prescription of corticosteroids. Recently, several cases of ICI-related cardiotoxicity have been reported with complications ranging from cardiogenic shock to sudden death. The true incidence of ICI-associated myocarditis is likely underestimated, due to a combination of factors including the lack of specificity in the clinical presentation, the potential of overlap with other cardiovascular and general medical illnesses, the challenges in the diagnosis, and a general lack of awareness of this condition. Currently, there are no clear guidelines for surveillance, diagnosis, or management of this entity. There are multiple unresolved issues including, but not limited to, identifying those at risk of this uncommon toxicity, elucidating the pathophysiology, determining if and what type of surveillance is appropriate, optimal work-up of suspected patients, and methods for resolution of myocarditis. Here we describe a clinical vignette and discuss the salient features and management strategies of ICI-associated myocarditis. The Oncologist 2018;23:518-523 KEY POINTS• The incidence of immune checkpoint inhibitor (ICI)-associated myocarditis is unclear and has been reported to range from 0.06% to 1% of patients prescribed an ICI.• Myocarditis may be difficult to diagnose.• The risk factors for ICI-associated myocarditis are not well understood but may include underlying autoimmune disease and diabetes mellitus. • The prevalence of myocarditis has been reported to be higher with combination immune therapies.• Myocarditis with ICI's typically occurs early, with an elevated troponin, may present with an normal left ventricular ejection fraction and may have a fulminant course.• The optimal management of myocarditis associated with ICI's is unclear but most cases are treated with high-dose steroids. PATIENT STORYA 41-year-old woman with no cardiac risk factors but a prior history of Hashimoto's thyroiditis was diagnosed with metastatic melanoma. She presented with mild dyspnea 6 days after completing four cycles of combined immune checkpoint inhibitor (ICI) therapy with ipilimumab and nivolumab. On exam, she was tachycardic and mildly volume overloaded but was otherwise stable. Sinus tachycardia was noted on electrocardiogram (ECG); there were no conduction abnormalities (Fig. 1A). Cardiac troponin I (cTn) was mildly elevated with normal level of N-terminal-pro brain natriuretic peptide (NT-proBNP). A chest computed tomography (CT) scan did not show evidence of pneumonitis but did show cardiomegaly and pulmonary congestion. An echocardiogram revealed global left...

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Comparative immunologic characterization of autoimmune giant cell myocarditis with ipilimumab

Cited by 50 publications

References 20 publications

Myocarditis in Cynomolgus Monkeys Following Treatment with Immune Checkpoint Inhibitors

Myocarditis in Cynomolgus Monkeys Following Treatment with Immune Checkpoint Inhibitors

Myocarditis Associated with Immune Checkpoint Inhibitors: An Expert Consensus on Data Gaps and a Call to Action

Immune Checkpoint Inhibitor-Associated Myocarditis

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