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 but 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 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 conduction 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.

Grant Number: 5R01HL156021-05
NIH Institute/Center: NIH
Principal Investigator: Justin Balko