权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
Justin M Balko
金额：
$ 82.04万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
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

来源：
https://reporter.nih.gov/project-details/10386891
关键词：
Ablation Adoptive Transfer Affect Aftercare Antigen Targeting Antigens Arrhythmia Attenuated Autoimmune Autoimmunity Automobile Driving Benefits and Risks Biological Biological Markers Blocking Antibodies CD8-Positive T-Lymphocytes CD8B1 gene CTLA4 gene Cardiac Cardiology Cardiovascular Diseases Cardiovascular system Cell Line Cells Cessation of life Clinical Complication Data Death Rate Development Etiology Event Fatality rate Functional disorder Genes Genetic Grant Heart Human Immune Immune Targeting Immune checkpoint inhibitor Immune system Immunologics Immunologist Immunology Immunotherapy Infiltration Inflammatory International Interruption Lead Ligands Malignant Neoplasms Modeling Monoclonal Antibodies Mus Muscle Muscle Cells Myelogenous Myocardial Myocarditis Myocardium Myositis Oncologist Oncology PDL1 pathway Pathogenesis Pathogenicity Pathologic Pathology Patients Phenocopy Phenotype Play Population Pre-Clinical Model Prevention strategy Receptor Activation Risk Management Role Sampling Scientist Self Tolerance Skeletal Muscle Specimen Striated Muscles T-Cell Activation T-Cell Development T-Cell Receptor T-Lymphocyte Testing Therapeutic Thymus Gland Tissue Banks Toxic effect Transcript Translating Tumor-infiltrating immune cells Wild Type Mouse body system cancer immunotherapy cancer therapy cancer type checkpoint therapy cytotoxic CD8 T cells early onset effective therapy experience experimental study heart damage human tissue immune-related adverse events improved insight macrophage mouse model new technology peripheral tolerance pre-clinical programmed cell death ligand 1 programmed cell death protein 1 receptor reconstitution response screening side effect single cell technology single-cell RNA sequencing success systemic autoimmunity treatment strategy

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