R01HL156021

Immunologic and Antigenic Drivers of Immune Checkpoint Inhibitor-Associated Myocarditis - Project Summary/Abstract

This proposal brings together Dr. Javid Moslehi, a cardio-oncologist and myocyte biologist, and Dr. Justin Balko, a cancer biologist and immunologist, to define the immunologic and antigenic drivers of myocarditis associated with cancer immunotherapies. Specifically, immune checkpoint inhibitors (ICI), which block the activity of immune 'brakes', such as CTLA-4 or PD-1, have revolutionized treatment for many cancer types. However, by activating the immune system, they can lead to autoimmune phenomena, called immune-related adverse events.

Our group has defined the clinical features of ICI-associated myocarditis, characterized by T cell and macrophage infiltration into the myocardium, fulminant arrhythmias, concurrent myositis, and a high fatality rate. To study this entity in more depth, we have generated pre-clinical mouse models that recapitulate ICI-associated myocarditis. Specifically, a genetic mouse model, where the genes for PD-1 (PDCD1) and CTLA-4 (CTLA4) are deleted, leads to early death due to myocarditis, which recapitulates human ICI-myocarditis clinically and pathologically.

Surprisingly, the mice do not have systemic autoimmunity; rather, the T cell infiltration is limited to the cardiovascular system and specifically the heart. Similarly, the infiltration seen in patients is often limited to T cell and macrophage infiltration into striated muscle, namely the heart and skeletal muscle. In this grant, we hypothesize that specific CD8+ T cell infiltrates restricted to one or more myocardial antigens are the drivers of pathogenesis in ICI-myocarditis. We seek to define the T cells responsible for the etiology and pathogenesis of ICI-myocarditis and to demonstrate that specific T cell populations are both necessary and sufficient to drive pathogenesis (Aim 1). Additionally, we seek to define the antigen targets of ICI-myocarditis in mice and in patients (Aim 2).

We leverage a team of experts in cardiology, oncology, and immunology to test our hypothesis through the conduct of these studies. In addition, we have leveraged a large international network of collaborators to collect cases of ICI-associated myocarditis. The overwhelming success of ICI is hampered in some patients by the development of fulminant toxicities, including ICI-myocarditis. This proposal will allow us to generate insights into the mechanisms of this entity, which we feel can translate into more effective treatment and prevention strategies.

In addition, the unique team of clinicians and scientists we have assembled for this proposal allows incorporation of new technology, which will allow better interrogation of the interactions between the cardiovascular and immune systems, translating into better insights in other forms of inflammatory cardiovascular diseases.

Vanderbilt University Medical Center

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Nashville, Tennessee 37203 United States

Single Zip Code

Improving Outcomes in Cancer Treatment-Related Cardiotoxicity (R01 Clinical Trial Optional) (PA-19-112)

Amendment Since initial award the total obligations have increased 443% from $748,855 to $4,067,768.