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.

项目总结/文摘