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：
10219907
负责人：
Justin M Balko
金额：
$ 83.21万
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/10219907
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 Structure 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.

项目概要/摘要这项提案汇集了心脏肿瘤学家和肌细胞生物学家 Javid Moslehi 博士和 Justin Balko 博士，癌症生物学家和免疫学家，定义心肌炎相关的免疫学和抗原驱动因素具体来说，是免疫检查点抑制剂（ICI），它可以阻断免疫活性。 CTLA-4 或 PD-1 等“刹车”彻底改变了许多癌症类型的治疗方法，但通过激活免疫系统，它们可以导致自身免疫现象，称为免疫相关不良事件。定义了 ICI 相关心肌炎的临床特征，其特征是 T 细胞和巨噬细胞浸润进入心肌、暴发性心律失常、并发肌炎和高死亡率。更深入地说，我们已经生成了可概括 ICI 相关心肌炎的临床前小鼠模型：具体来说，删除了 PD-1 (Pdcd1) 和 CTLA-4 (Ctla4) 基因的遗传小鼠模型，导致因心肌炎而过早死亡，这在临床和病理学上概括了人类 ICI 心肌炎。令人惊讶的是，小鼠没有全身性自身免疫；相反，T 细胞浸润仅限于心血管系统，特别是心脏，类似地，患者中看到的浸润通常仅限于 T。细胞和巨噬细胞浸润到横纹肌，即心脏和骨骼肌。特定的 CD8+ T 细胞浸润仅限于一种或多种心肌抗原，是 ICI 心肌炎的发病机制我们试图确定负责 ICI 心肌炎病因和发病机制的 T 细胞。 ICI-心肌炎并证明特定的 T 细胞群对于驱动是必要且充分的此外，我们还试图确定小鼠和体内 ICI 心肌炎的抗原靶标。我们利用心脏病学、肿瘤学和免疫学专家团队来检验我们的假设。此外，通过进行这些研究，我们还利用了庞大的国际合作者网络。收集 ICI 相关心肌炎病例。 ICI 的巨大成功在一些患者中受到暴发性毒性的发展的阻碍，包括 ICI-心肌炎。该提案将使我们能够深入了解该实体的机制，我们认为这可以转化为更有效的治疗和预防策略此外，独特的团队。我们为这项提案聚集了圣人和科学家，允许结合新技术将允许更好地探究心血管和免疫系统之间的相互作用，并将其转化为对其他形式的炎症性心血管疾病有更好的见解。