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

• 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
• 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

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.

项目摘要/摘要 免疫检查点抑制剂（ICI）代表癌症护理的范式转移，利用免疫系统 靶向癌细胞。在动物和基础研究中，这些途径（PD-1，PD-L1和CTLA-4）也很关键 动物研究中的动脉粥样硬化和PD-1，PD-L1和CTLA-4的封锁的负调节剂激活T 导致T细胞浸润并增加动脉粥样硬化的细胞。我们提供回顾性的临床和成像 数据支持我们的假设，即ICI将在一项前瞻性研究中增加冠状动脉粥样硬化。我们将 通过进行前瞻性观察冠状动脉CTA研究来检验这一假设，其中有135例患者（最初 招募300）患有黑色素瘤，有和没有BRAF突变（2：1的比例，ICI/BRAF），将经历系列 基线时冠状动脉CTA，12个月（子组）和2年。患有BRAF突变的黑色素瘤患者 接受BRAF抑制剂并将充当对照组，而BRAF阴性患者则接受ICI治疗。 在AIM 2中，基于先前的工作，我们将测试预先指定的合理生物学因素 与斑块进展的关联（例如PD-1，PD-L1，SCD163，SCD14，MCP-1，IL-6，IL-1B）介导 通过ICI加速了动脉粥样硬化。例如，较低的PD-1和PD-L1水平与较高 冠状动脉粥样硬化斑块，其中PD-1和PD-L1均可抑制斑块中T细胞驱动的炎症 和斑块进展。在AIM 3中，我们将执行应用单细胞RNA的公正探索性分析 系统地破译有助于的免疫核管的技术。在患者中，不是在ICI上，特定的t 细胞子集已与动脉粥样硬化有关，在初步数据中，我们显示了特定T细胞的激活 （CD8+）具有其他ICI战术。 ICI的使用增加并继续迅速扩展。估计 目前，有36％的癌症患者有资格参加ICI和利用主动临床试验的数量 ICI是非凡的。因此，迫切需要在临床研究中测试ICI是否导致 加速的冠状动脉粥样硬化，并深入了解所涉及的机制。