Immunologic and antigenic drivers of immune checkpoint inhibitor-associated myocarditis
Ended Project Grant Awarded Last action
- Award ID
- R01HL156021
- Recipient
-
Vanderbilt University Medical Center UEI GYLUH9UXHDX5
- Awarding agency
-
National Heart Lung and Blood Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $12,211,947
Award facts
- Assistance listing
- 93.837 Cardiovascular Diseases Research
- Completion date
- Originally
- Funding
-
- $11,379,886.00 Federal
- $832,061.00 Non-federal
- Place of performance
- Nashville, TN 37203, USA
Award details come from USAspending.gov.
Description
- 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.
Transactions
| Action | Federal | Non-federal | Date |
|---|---|---|---|
| Amendment | $0 | $0 | |
| Amendment | $849,674 | $0 | |
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| Amendment | $729,493 | $0 | |
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| Amendment | $815,509 | $0 | |
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| Amendment | $820,373 | $0 | |
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| Amendment | $83,206 | $0 | |
| Amendment | $83,206 | $83,206 | |
| Amendment | $748,855 | $0 | |
| Original award | $748,855 | $748,855 |
Show all 25
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Mayo Clinic | $16,040 | |
| The Regents Of The University Of California. San Francisco | $394,223 | |
| The Regents Of The University Of California. San Francisco | $331,075 | |
| The Regents Of The University Of California. San Francisco | -$96,900 | |
| The Regents Of The University Of California. San Francisco | $372,579 | |
| The Regents Of The University Of California. San Francisco | $128,008 |
Quick answers
Who received award R01HL156021?
R01HL156021 was awarded to Vanderbilt University Medical Center by National Heart Lung and Blood Institute (National Institutes of Health) on May 1, 2021.
How much is award R01HL156021 worth?
$12,211,947 has been obligated on R01HL156021: $11,379,886 in federal funding and $832,061 in non-federal funding.
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