Immunologic and Antigenic Drivers of Immune Checkpoint Inhibitor-Associated Myocarditis

免疫检查点抑制剂相关心肌炎的免疫学和抗原驱动因素

基本信息

  • 批准号:
    10386891
  • 负责人:
  • 金额:
    $ 82.04万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-05-01 至 2026-04-30
  • 项目状态:
    未结题

项目摘要

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.
项目总结/文摘

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Justin M Balko其他文献

Justin M Balko的其他文献

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{{ truncateString('Justin M Balko', 18)}}的其他基金

Immunologic and Antigenic Drivers of Immune Checkpoint Inhibitor-Associated Myocarditis
免疫检查点抑制剂相关心肌炎的免疫学和抗原驱动因素
  • 批准号:
    10618791
  • 财政年份:
    2021
  • 资助金额:
    $ 82.04万
  • 项目类别:
Immunologic and Antigenic Drivers of Immune Checkpoint Inhibitor-Associated Myocarditis
免疫检查点抑制剂相关心肌炎的免疫学和抗原驱动因素
  • 批准号:
    10219907
  • 财政年份:
    2021
  • 资助金额:
    $ 82.04万
  • 项目类别:
(PQ8) Patient- and tumor-specific biomarkers and mechanisms that predict irAEs resulting from checkpoint inhibition
(PQ8) 患者和肿瘤特异性生物标志物和预测检查点抑制引起的 irAE 的机制
  • 批准号:
    9891975
  • 财政年份:
    2019
  • 资助金额:
    $ 82.04万
  • 项目类别:
(PQ8) Patient- and tumor-specific biomarkers and mechanisms that predict irAEs resulting from checkpoint inhibition
(PQ8) 患者和肿瘤特异性生物标志物和预测检查点抑制引起的 irAE 的机制
  • 批准号:
    10590676
  • 财政年份:
    2019
  • 资助金额:
    $ 82.04万
  • 项目类别:
(PQ8) Patient- and tumor-specific biomarkers and mechanisms that predict irAEs resulting from checkpoint inhibition
(PQ8) 患者和肿瘤特异性生物标志物和预测检查点抑制引起的 irAE 的机制
  • 批准号:
    10133451
  • 财政年份:
    2019
  • 资助金额:
    $ 82.04万
  • 项目类别:
(PQ8) Patient- and tumor-specific biomarkers and mechanisms that predict irAEs resulting from checkpoint inhibition
(PQ8) 患者和肿瘤特异性生物标志物和预测检查点抑制引起的 irAE 的机制
  • 批准号:
    10359717
  • 财政年份:
    2019
  • 资助金额:
    $ 82.04万
  • 项目类别:
Dusp4 in breast cancer: tumor suppressor biology and therapeutic strategies
Dusp4 在乳腺癌中的作用:肿瘤抑制生物学和治疗策略
  • 批准号:
    8765222
  • 财政年份:
    2014
  • 资助金额:
    $ 82.04万
  • 项目类别:
Dusp4 in breast cancer: tumor suppressor biology and therapeutic strategies
Dusp4 在乳腺癌中的作用:肿瘤抑制生物学和治疗策略
  • 批准号:
    9044055
  • 财政年份:
    2014
  • 资助金额:
    $ 82.04万
  • 项目类别:
Dusp4 in breast cancer: tumor suppressor biology and therapeutic strategies
Dusp4 在乳腺癌中的作用:肿瘤抑制生物学和治疗策略
  • 批准号:
    9268419
  • 财政年份:
    2014
  • 资助金额:
    $ 82.04万
  • 项目类别:
Dusp4 in breast cancer: tumor suppressor biology and therapeutic strategies
Dusp4 在乳腺癌中的作用:肿瘤抑制生物学和治疗策略
  • 批准号:
    9061648
  • 财政年份:
    2014
  • 资助金额:
    $ 82.04万
  • 项目类别:

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