Immunologic and Antigenic Drivers of Immune Checkpoint Inhibitor-Associated Myocarditis

项目总结/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 Baglio博士， 一位癌症生物学家和免疫学家，以确定与心肌炎相关的免疫和抗原驱动因素， 癌症免疫疗法具体地说，免疫检查点抑制剂（ICI），它阻断免疫细胞的活性， “刹车”，如CTLA-4或PD-1，已经彻底改变了许多癌症类型的治疗，但通过激活肿瘤细胞， 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。我们集团 定义了ICI相关性心肌炎的临床特征，其特征为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，病死率高。研究这个实体 更深入地说，我们已经产生了临床前小鼠模型，概括了ICI相关的心肌炎： 具体地，其中PD-1（Pdcd 1）和CTLA-4（Ctla 4）的基因缺失的遗传小鼠模型导致 早期死亡的心肌炎，重演人类ICI-心肌炎的临床和病理。 令人惊讶的是，小鼠不具有全身性自身免疫;相反，T细胞浸润仅限于免疫系统。 心血管系统，特别是心脏。同样，在患者中观察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。在这份协议中，我们 假设局限于一种或多种心肌抗原的特异性CD 8 + T细胞浸润是 ICI-心肌炎的发病机制。我们试图确定T细胞负责的病因和发病机制， ICI-心肌炎，并证明特定的T细胞群是必要的和足够的驱动， 发病机制（目的1）。此外，我们试图确定ICI-心肌炎的抗原靶点， 患者（目标2）。我们利用心脏病学、肿瘤学和免疫学的专家团队来验证我们的假设 通过开展这些研究。此外，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的压倒性成功在一些患者中受到暴发性毒性的发展的阻碍， 包括心肌梗死这一提议将使我们能够深入了解这一实体的机制， 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 我们为这项提案召集的临床医生和科学家的参与，允许纳入新技术， 将允许更好地询问心血管和免疫系统之间的相互作用， 对其他形式的炎症性心血管疾病有更好的见解。

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.