Immune checkpoint inhibitors and accelerated coronary atherosclerosis

免疫检查点抑制剂与加速冠状动脉粥样硬化

基本信息

批准号：
10612938
负责人：
Tomas G Neilan
金额：
$ 97.8万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612938
关键词：
Acceleration Adrenal Cortex Hormones Age Animals Aorta Arterial Fatty Streak Atherosclerosis Automobile Driving BRAF gene Bioinformatics Biological Factors Biological Markers Biology CCL2 gene CD8B1 gene CTLA4 gene Calcium Cancer Patient Cardiac Cardiovascular system Cells Characteristics Clinical Clinical Data Clinical Research Clinical Trials Coagulation Process Control Groups Coronary Coronary Arteriosclerosis Data Diabetes Mellitus Disease Dose Eligibility Determination Endothelium Enrollment Event Fibrin fragment D Genomics Glycosylated hemoglobin A HIV Hypertension Image Immune Immune checkpoint inhibitor Immune system Immunologic Markers Immunology Inflammation Insulin Interleukin-6 Intervention Trial Lead Link Lipids Malignant Neoplasms Measurement Measures Mediating Modeling Morphology Mutate Mutation Observational Study Oncology PD-1 blockade Participant Particle Size Pathway interactions Patients Persons Prospective Studies RNA Randomized Retrospective Studies Risk Serum Specific qualifier value Subgroup T cell infiltration T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Technology Testing Thromboplastin Time Toxic effect Troponin Vascular Cell Adhesion Molecule-1 Work animal data attenuation cancer care cancer cell cohort coronary computed tomography angiography coronary plaque density high risk immune activation immune checkpoint immune checkpoint blockade immune function immune-related adverse events indexing inhibitor innovation insight lipoprotein-associated phospholipase A(2)melanoma oxidized low density lipoprotein programmed cell death ligand 1 programmed cell death protein 1 progression risk prospective recruit tumor progression

项目摘要

Project Summary/Abstract Immune checkpoint inhibitors (ICI’s) represent a paradigm shift in cancer care, leveraging the immune system to target cancer cells. In animal and basic studies, these pathways (PD-1, PD-L1 and CTLA-4) are also critical negative regulators of atherosclerosis and blockade of PD-1, PD-L1 and CTLA-4 in animal studies activates T cells leading to T cell infiltration and increased atherosclerosis. We provide retrospective clinical and imaging data to support our hypothesis that ICI’s will increase coronary atherosclerosis in a prospective study. We will test this hypothesis by performing a prospective observational coronary CTA study, where 135 patients (initially enrolling 300) with melanoma, with and without the BRAF mutation (2:1 ratio, ICI/BRAF), will undergo serial coronary CTA at baseline, 12 months (sub-group) and 2 years. Patients with melanoma with a BRAF mutation receive BRAF inhibitors and will act as the control group, while BRAF negative patients are treated with an ICI. In Aim 2, based on prior work, we will test whether pre-specified plausible biological factors with established associations with plaque progression (e.g. PD-1, PD-L1, sCD163, sCD14, MCP-1, IL-6, IL-1b) mediate the accelerated atherosclerosis with ICI’s. For example, lower PD-1 and PD-L1 levels associate with higher coronary atherosclerotic plaque where both PD-1 and PD-L1 suppress T cell–driven inflammation in plaques and plaque progression. In Aim 3, we will perform unbiased exploratory analyses applying single-cell RNA technologies to systematically decipher the immune cells that contribute. In patients, not on an ICI, specific T cell subsets have been linked to atherosclerosis and, in preliminary data, we show activation of specific T cells (CD8+) with other ICI toxicities. The use of ICI’s has increased and continues to rapidly expand. It is estimated that 36% of cancer patients are currently eligible for an ICI and the number of active clinical trials leveraging ICIs is extraordinary. Therefore, there is an urgent need to test in a clinical study whether ICI’s lead to accelerated coronary atherosclerosis and to provide insight into the mechanisms involved.

项目概要/摘要免疫检查点抑制剂 (ICI) 代表了癌症治疗的范式转变，利用了免疫系统在动物和基础研究中，这些通路（PD-1、PD-L1 和 CTLA-4）也至关重要。动物研究中动脉粥样硬化的负调节因子以及 PD-1、PD-L1 和 CTLA-4 的阻断可激活 T 我们提供回顾性临床和影像学服务。我们将在一项前瞻性研究中提供数据来支持我们的假设，即 ICI 会增加冠状动脉粥样硬化。通过进行前瞻性观察性冠状动脉 CTA 研究来检验这一假设，其中 135 名患者（最初招募 300 名患有黑色素瘤的患者，无论有或没有 BRAF 突变（比例为 2:1，ICI/BRAF），都将接受系列治疗患有 BRAF 突变的黑色素瘤患者在基线、12 个月（亚组）和 2 岁时进行冠状动脉 CTA。接受 BRAF 抑制剂的患者将作为对照组，而 BRAF 阴性患者则接受 ICI 治疗。在目标 2 中，基于先前的工作，我们将测试预先指定的合理生物因素是否与既定的与斑块进展的关联（例如 PD-1、PD-L1、sCD163、sCD14、MCP-1、IL-6、IL-1b）介导例如，较低的 PD-1 和 PD-L1 水平与较高的 ICI 相关。冠状动脉粥样硬化斑块，其中 PD-1 和 PD-L1 抑制斑块中 T 细胞驱动的炎症在目标 3 中，我们将应用单细胞 RNA 进行公正的探索性分析。系统地破译患者体内而不是 ICI 上的特异性 T 细胞的技术。细胞亚群与动脉粥样硬化有关，在初步数据中，我们显示特定 T 细胞的激活 (CD8+) 与其他 ICI 毒性据估计，ICI 的使用已增加并继续迅速扩大。目前 36% 的癌症患者有资格接受 ICI，并且利用积极的临床试验数量因此，迫切需要通过临床研究来测试 ICI 是否会导致疾病。加速冠状动脉粥样硬化并提供对相关机制的深入了解。