Mathematical modelling of autoimmune myocarditis and the effects of immune checkpoint inhibitors

Autoimmune myocarditis is a rare, but frequently fatal, side-effect of immune checkpoint inhibitors (ICIs), a class of drugs used to treat cancer. Due to the overwhelming complexity of the immune system, this condition is not well understood, despite the significant research efforts devoted to it. To better understand ICI-induced autoimmune myocarditis, we suggest a new approach: mathematical modelling. Mathematical modelling of myocarditis can help determine which parts of the immune system are critical to the development and progression of the disease and therefore warrant further investigation. In this paper, we aim to provide the immunological background needed to develop a mathematical model of this disease and review relevant existing models of immunology that serve as the mathematical inspiration needed to start this effort.

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Immune checkpoint inhibition-induced myocarditis in cancer patients: Proposal of a detection and management strategy.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15116 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15116-e15116 ◽

Cited By ~ 1

Author(s):

Anjali Rao ◽

Vlad Zaha ◽

Bonnie Bermas ◽

John Lohrey ◽

Kevin Dale Courtney ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Systolic Dysfunction ◽

Retrospective Chart Review ◽

High Dose ◽

Imaging Data ◽

Autoimmune Myocarditis ◽

Multi Disciplinary Team ◽

Steroid Sparing

e15116 Background: Monoclonal antibodies against the immune checkpoint inhibitors (ICI) programmed cell death protein-1 (PD-1), its ligand (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4) have had a transformative effect on the field of oncology. Autoimmune myocarditis (AIM) is a rare but potentially severe complication associated with these medications, without specific management guidelines. The aim of this observational report is to present four cases of AIM following ICI and propose a detection and treatment strategy. Methods: Four patients who received anti-PD-1 or anti-PD-L1 immune checkpoint inhibitors (ICI) developed severe cardiac manifestations within two weeks to several months after initiation. Demographic, historical, laboratory, and imaging data were collected by retrospective chart review. Results: Manifestations included LV systolic dysfunction, ventricular arrhythmias, and elevated cardiac enzymes. Myocardial ischemia was ruled out by coronary catheterization. Abnormal myocardial tissue characteristics on CMRI and biopsy were used to establish the diagnosis of myocarditis. Patients had endocrine, rheumatologic and neurologic irAEs (Table) and were managed by a multi-disciplinary team including oncology, rheumatology and cardiology. Management included prompt administration of high-dose steroids with rapid taper. Steroid sparing and escalation therapies included mycophenolate mofetil, methotrexate, rituximab, abatacept (CTLA4 agonist), as well as plasma exchange. This combination of tiered therapies resulted in substantial improvement in AIM. Conclusions: Clinical improvements seen in these cases highlight potential key elements for controlling autoimmune myocarditis response to ICI. We propose rapid diagnosis including CMRI and biopsy and initiation of high dose prednisone. We also recommend prompt initiation of steroid sparing agent within one month of diagnosis. Importantly, these patients should be managed by a multi-disciplinary team. [Table: see text]

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Mathematical modelling of autoimmune myocarditis and the effects of immune checkpoint inhibitors

10.1101/2021.09.03.458857 ◽

2021 ◽

Author(s):

Solveig A. van der Vegt ◽

Liudmila Polonchuk ◽

Ken Wang ◽

Sarah L. Waters ◽

Ruth E. Baker

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Predictive Modelling ◽

Cancer Therapies ◽

Autoimmune Myocarditis ◽

Treatment Regimens ◽

Disease Characteristics ◽

Bifurcation Structures

AbstractAutoimmune myocarditis is a rare, but frequently fatal, side effect of immune checkpoint inhibitors (ICIs), a class of cancer therapies. Despite extensive experimental work on the causes, development and progression of this disease, much still remains unknown about the importance of the different immunological pathways involved. We present a mathematical model of autoimmune myocarditis and the effects of ICIs on its development and progression to either resolution or chronic inflammation. From this, we gain a better understanding of the role of immune cells, cytokines and other components of the immune system in driving the cardiotoxicity of ICIs. We parameterise the model using existing data from the literature, and show that qualitative model behaviour is consistent with disease characteristics seen in patients in an ICI-free context. The bifurcation structures of the model show how the presence of ICIs increases the risk of developing autoimmune myocarditis. This predictive modelling approach is a first step towards determining treatment regimens that balance the benefits of treating cancer with the risk of developing autoimmune myocarditis.

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Autoimmune Myocarditis Caused by Immune Checkpoint Inhibitors Treated With Antithymocyte Globulin

Journal of Immunotherapy ◽

10.1097/cji.0000000000000239 ◽

2018 ◽

Vol 41 (7) ◽

pp. 332-335 ◽

Cited By ~ 24

Author(s):

Varun Jain ◽

Mahsa Mohebtash ◽

Maria E. Rodrigo ◽

George Ruiz ◽

Michael B. Atkins ◽

...

Keyword(s):

Immune Checkpoint ◽

Antithymocyte Globulin ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Autoimmune Myocarditis

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Immune Checkpoint Inhibitors and Cardiac Toxicity: An Emerging Issue

Current Medicinal Chemistry ◽

10.2174/0929867324666170407125017 ◽

2018 ◽

Vol 25 (11) ◽

pp. 1327-1339 ◽

Cited By ~ 47

Author(s):

Gilda Varricchi ◽

Giancarlo Marone ◽

Valentina Mercurio ◽

Maria Rosaria Galdiero ◽

Domenico Bonaduce ◽

...

Keyword(s):

Immune Checkpoint ◽

Cardiac Dysfunction ◽

Immune Checkpoint Inhibitors ◽

Cardiac Toxicity ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Wide Spectrum ◽

Recent Experience ◽

Autoimmune Myocarditis ◽

Human Cardiomyocytes

Although survival of patients with different types of cancer has improved, cardiotoxicity induced by anti-neoplastic drugs remains a critical issue. Cardiac dysfunction after treatment with anthracyclines has historically been a major problem. However, also targeted therapies and biological molecules can induce reversible and irreversible cardiac dysfunction. Over the last years, cancer immunotherapies haverevolutionized the clinical management of a wide spectrum of solid and hematopoietic malignancies previously endowed with poor prognosis. Immune checkpoint inhibitors are at the forefront of immunotherapy: the two most prominent are the targeting of cytotoxic-T-lymphocyte-associated antigen 4 (CTLA- 4) and of programmed cell death 1 (PD-1) and its ligand PD-L1. Ipilimumab (anti-CTLA-4) is the godfather of checkpoint inhibitors, whereas several blocking monoclonal antibodies targeting PD-1 (nivolumab and pembrolizumab) and PD-L1 (atezolizumab, durvalumab, avelumab, and BMS-946559) have been developed. Inhibitors of CTLA-4 and PD-1/PD-L1 pathway can unleash anti-tumor immunity and mediate cancer regressions. Although CTLA-4 inhibitors and PD-1 and PD-L1 blocking agents are frequently associated with a wide spectrum of immune-related adverse events, cardiac toxicity has been underestimated. However, early animal studies have demonstrated that after CTLA-4 inhibition and PD-1 deletion autoimmune myocarditis can occur. Moreover, PD-1 and PD-L1 can be expressed in rodent and human cardiomyocytes. During the last years several cases of fatal heart failure have been documented in melanoma patients treated with checkpoint inhibitors. The recent experience with cardiovascular toxic effects associated with checkpoint inhibitors introduces important concepts biologically and clinically relevant for future oncology trials and clinical practice.

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