Long-Term Cardiovascular Sequelae of Cancer Immunotherapies

项目摘要/摘要 在这项建议中，我们将研究免疫检查点抑制剂(ICI)的长期心血管后遗症， 给癌症治疗带来革命性变化的疗法。我们将同时使用老鼠模型和癌症幸存者 接受ICI治疗。我们定义了急性T细胞介导的ICI心脏并发症，包括心肌炎， 心包炎和脉管炎是这些患者的重要临床问题。我们的初步数据表明 程序性死亡-1/配体-1(PD-1/PD-L1)在预防心肌损伤等心血管疾病中的作用 疾病。临床上，我们观察了ICI治疗后发生亚急性心脏损伤的患者。我们 假设PD-1/PD-L1通过ICI治疗被阻断，并与其他心脏损害一起恶化 长期的心血管健康。为了解决这个问题，我们将首先使用我们开发的两个鼠标模型 ICI-心肺毒性：ICI联合治疗的模型(MRL/MPJ)，以及 基因敲除模型(PD1-/-；CTLA+/-)。在目标1中，我们将检验心脏缺血的假设 增强我们的药物和遗传小鼠模型中免疫渗透和炎症的增加 (与适当的对照组相比)，在这些小鼠中进行深入的生理和免疫分析 模特们。我们利用这些机械性和临床前模型与Aim 2的转换端点，其中 我们将利用大量接受ICI治疗的长期幸存者(200名患者)的回顾队列来评估 ICI对心脏危险因素的影响，包括血压、体重、身体成分和冠状动脉 钙化。一项前瞻性队列(150名患者)将被累积用于纵向临床表型分析以确定 并验证临床终点，并扩展和验证这些发现。我们将进行强化心脏手术 (超声心动图、心脏MRI、高敏肌钙蛋白、C反应蛋白)和代谢(空腹血脂和 血糖)监测，特别是检验肌钙蛋白在ICI治疗早期升高的假设 与心室重塑、炎症和纤维化有关。在康复后死亡的患者中 心肌炎，我们将进行快速尸检，以确定炎症、纤维化、结构性的程度 变化，以及残留的免疫细胞群。 ICI的压倒性成功导致接受这些治疗的长期幸存者急剧增加。 探员们。这项建议将使我们能够表征ICI对长期心血管健康的影响，因此 促进制定适当的筛查、治疗和预防战略。

Project Summary/Abstract In this proposal, we will study the long-term cardiovascular sequelae of immune checkpoint inhibitors (ICI), therapies that have revolutionized cancer treatment. We will use both mouse models and cancer survivors treated with ICI. We have defined acute, T cell mediated cardiac complications of ICI, including myocarditis, pericarditis, and vasculitis as a significant clinical concern in these patients. Our preliminary data suggest a role for programmed death-1/ligand-1 (PD-1/PD-L1) in preventing myocardial injury and other cardiovascular disease. Clinically, we have observed patients with subacute cardiac injury following ICI treatment. We hypothesize that PD-1/PD-L1 blockade through ICI therapy, in conjunction with other cardiac insults, worsens long-term cardiovascular health. To address this, we will first utilize two mouse models that we have developed that recapitulate ICI-cardiopulmonary toxicities: a model (MRL/MpJ) treated with combination ICI therapy, and a genetic knockout model (PD1-/-; CTLA+/-). In Aim 1, we will test the hypothesis that cardiac ischemia potentiates increased immune infiltration and inflammation in our pharmacologic and genetic mouse models (compared to appropriate controls), performing in-depth physiologic and immune profiling in these mouse models. We leverage these mechanistic and pre-clinical models with translational endpoints for Aim 2, where we will utilize a large retrospective cohort of long-term survivors treated with ICI (200 patients) to assess the impact of ICI on cardiac risk factors, including blood pressure, weight, body composition, and coronary artery calcification. A prospective cohort (150 patients) will be accrued for longitudinal clinical phenotyping to identify and validate clinical endpoints and to extend and validate these findings. We will perform intensive cardiac (echocardiography, cardiac MRI, high-sensitivity troponin, C-reactive protein) and metabolic (fasting lipids and glucose) monitoring, specifically testing the hypothesis that troponin elevation early in treatment with ICI correlates with ventricular remodeling, inflammation, and fibrosis. In patients who die following recovery from myocarditis, we will perform rapid autopsies to determine the extent of inflammation, fibrosis, structural changes, and residual immune cell populations. The overwhelming success of ICI has led to a dramatic increase of long-term survivors treated with these agents. This proposal will allow us to characterize the effects of ICI on long-term cardiovascular health, thus enabling development of appropriate screening, treatment, and prevention strategies.