Noninvasive Diagnosis of Immune Checkpoint Inhibitor-Associated Myocarditis
Abstract
Immunotherapy has revolutionized cancer treatment such as advanced bladder, head and neck, and blood cancers. However, many patients face serious immune-related adverse events, including cardiovascular complications. Indeed, myocarditis (inflammation of the heart muscle) is one of the most feared complications of immunotherapy. Myocarditis occurs in approximately 1% of treated patients, but mortality can be as high as 50%. Given the rise in the use of immunotherapeutics (tens of thousands of cancer patients have been treated with immunotherapeutics in the past few years and the number is increasing), there has been a significant increase in the reported cases of myocarditis. Nowadays, diagnosis of myocarditis is done through biopsies, and echocardiography, and cardiac magnetic resonance imaging (MRI). Endomyocardial biopsies are invasive and prone to complications and non-diagnostic results and therefore, are challenging to use to assess response to therapy. Cardiac MRI is currently the preferred imaging modality for the diagnosis of myocarditis. However, recent data found the cases of myocarditis are being missed by using cardiac MRI alone. This limits the ability to understand the syndrome or develop tools as predictors for these potentially fatal events. Therefore, the development of a non-invasive method to detect inflammation and track specific subsets of immune cells in the myocardial tissue, which are relevant in the development of the disease, is a critical unmet need. Such an approach would enable early and prompt recognition and treatment of this potentially fatal disease. Here, we aim to develop a novel, whole-body imaging approach to detect myocardial inflammation via targeting immune markers associated with the disease. The approach can revolutionize the way we diagnose this fatal cancer immunotherapy-associated side effect. Furthermore, results will help us to better understand how the immune landscape in the myocardium changes in response to immunotherapy and to establish criteria to define levels of severity of the syndrome and its consequences on cardiac function. The PI started his independent career as an Assistant Professor at the Dana-Farber Cancer Institute and Harvard Medical School in the summer of 2019. Support for this application will help us to establish the lab at the forefront of cancer immunotherapy and cancer imaging. In the long term, we aim to better understand why some patients respond to therapy and why some do not, to help understand what results in an immunosuppressive or an anti-tumor immune microenvironment, and to develop more effective therapies and new prognostic modalities for early assessment of the response to treatment. We aim to bring a unique perspective to the field of tumor immunology and make important contributions to efforts that seek to translate preclinical immunology to the clinic. In this effort, we will apply our experience and expertise in immunology and chemical biology in a unique and innovative way. This proposal will tackle the overarching challenge of transforming cancer treatment through improving immunotherapy and eliminating the risks of therapy-associated toxicity. The use of immunotherapy is on the rise and therefore, a reliable approach to detect myocarditis is critically needed. Accurate and prompt diagnosis of immunotherapy-associated myocarditis will save lives, including military personnel and other military beneficiaries. The proposed approach, to detect myocarditis by virtue of detecting infiltrating immune cells in the myocardium, would be a paradigm shift and can significantly decrease or completely eliminate the risk of therapy-associated fatality. We will use mice as a model of the human body to help us gain this understanding without harming any patients. We plan to use mice models that develop myocarditis which recapitulate what occurs in the clinic. We will then image these mice to detect infiltration of specific subsets of immune cell
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210459
Entities
People
- Mohammad Rashidian
Organizations
- Dana–Farber Cancer Institute
- United States Army