Mechanisms of cancer immunotherapy-associated thrombosis

癌症免疫治疗相关血栓形成的机制

基本信息

批准号：
10667046
负责人：
Claudia Marcela Diaz-Montero
金额：
$ 72.14万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667046
关键词：
Address Agonist Animal Model Blood Blood Platelets Blood Vessels Blood coagulation Body mass index CTLA4 gene Cancer Patient Cell Separation Cell model Cells Chemotherapy and/or radiation Clinical Coagulation Process Complication Development Disease Endothelial Cells Endothelium Fibrin fragment D Frequencies Gene Expression Generations Goals Hemoglobin Histone H3 Human IL8 gene Immune Immune System Diseases Immune checkpoint inhibitor Immunoglobulin G Immunologic Surveillance Immunophenotyping Immunotherapy In Vitro Incidence Incubated Inflammation Inflammatory Interferon Type II Knowledge Laboratory Study Leukocytes Malignant Neoplasms Measures Mediating Modeling Monoclonal Antibodies Morbidity - disease rate Mouse Strains Mus Myelogenous Myeloid Cells Newly Diagnosed Pathogenesis Pathway interactions Patients Plasma Platelet Activation Platelet Count measurement Platelet aggregation Population Prevention approach Prothrombin Publishing Reporting Risk Risk Assessment Role Sampling Source System T-Lymphocyte Thrombin Thromboplastin Thrombosis Thrombus Tumor Immunity Vascular Cell Adhesion Molecule-1 Venous Thrombosis White Blood Cell Count procedure anti-PD1 antibodies antithrombin III-protease complex cancer cell cancer diagnosis cancer immunotherapy cancer risk cancer therapy cancer type cell type checkpoint therapy clinically relevant cohort cytokine extracellular extracellular vesicles forging genetic regulatory protein high risk immune-related adverse events immunoregulation inflammatory marker monocyte mortality mouse model neoplastic cell neutrophil novel strategies patient stratification peripheral blood potential biomarker programmed cell death ligand 1 programmed cell death protein 1 prospective response side effect thromboinflammation tumor venous thromboembolism

项目摘要

Cancer immunotherapy is one of the most important advances in cancer treatment in decades, and has rapidly moved to front-line therapy for many cancers. The mechanism of cancer immunotherapy is to disable normal immunoregulatory pathways through administration of Immune Checkpoint Inhibitors (ICI), which are monoclonal antibodies directed toward key immune regulatory proteins including PD-1, PD-L1 and CTLA-4. Disabling these pathways enhances anti-tumor immunity. However, since these responses are not tumor-specific, ICIs are associated with a variety of immune-related adverse events (irAEs). We and others have recently reported a high incidence of thrombosis, which may exceed 20%, in patients treated with ICI; given the increasing use of ICIs in cancer treatment and the frequency of cancer diagnoses, it is clear that ICI-Cancer Associated Thrombosis (ICI-CAT) has become a major clinical problem and that better understanding of this disorder is urgently needed. However, there is little information available concerning mechanisms of ICI-CAT, and there are no published studies addressing this issue. We hypothesize that ICI-CAT is an irAE resulting from ICI-induced cellular activation and prothrombotic activity in the setting of underlying tumor-associated inflammation. Our murine model demonstrates that ICI-CAT requires the presence of an underlying tumor, with markedly increased expression of tumor cell tissue factor (TF) occurring after ICI treatment. Our model also supports a role for neutrophil extracellular traps (NETs) and platelet activation in ICI-CAT; platelet activation is also suggested in patients treated with ICI by our demonstration of increased levels of circulating platelet-neutrophil aggregates. On a cellular level, anti-PD-1 antibodies stimulate neutrophil NET release and prothrombotic activity, and may also enhance platelet activation in the presence of subthreshold thrombin concentrations. In this application, we propose to advance our understanding of ICI-CAT using both cellular and animal models, and to extend these studies to clinical samples from patients before and after initiating treatment with ICI. In Aim 1, we will determine the effect of different ICI and ICI combinations on the development of thrombi in tumor-bearing mice, and assess our model using other tumor types and mouse strains. We will examine thrombus size and composition, and identify critical cell types involved in thrombus formation by depleting mice of T cells, neutrophils, monocytes or platelets. We will also further define the cellular mechanisms involved in expression of prothrombotic activity using isolated leukocytes from normal human donors, mixed leukocyte populations, and endothelial cells, incubated with cytokines and ICI. In Aim 2, we will extend these studies by measuring mechanistic markers of inflammation and vascular activation in patient plasma before and after initiating ICI, and by comparing procoagulant gene expression in myeloid cells from patients treated with ICI who did, or did not develop thrombosis. Taken together, these studies should provide important new information leading to better understanding of mechanisms, and potentially new approaches for prevention and treatment of ICI-CAT.

癌症免疫疗法是几十年来癌症治疗中最重要的进步之一，并且迅速移至许多癌症的前线治疗。癌症免疫疗法的机制是禁用正常通过给予免疫检查点抑制剂（ICI）的免疫调节途径，它是单克隆针对关键免疫调节蛋白（包括PD-1，PD-L1和CTLA-4）的抗体。禁用这些途径增强了抗肿瘤免疫力。但是，由于这些反应不是肿瘤特异性的，因此ICI是与各种与免疫相关的不良事件（IRAE）相关。我们和其他人最近报告了在接受ICI治疗的患者中，血栓形成的高发病率可能超过20％；考虑到越来越多的使用癌症治疗中的ICI和癌症诊断的频率很明显，ICI-Canter相关血栓形成（ICI-CAT）已成为一个主要的临床问题，对这种疾病的更好理解是迫切需要。但是，几乎没有有关ICI-Cat机制的信息，并且有没有针对此问题的发表研究。我们假设ICI-cat是由ICI诱导的IRAE 在潜在的肿瘤相关炎症的情况下，细胞激活和促血栓性活性。我们的鼠模型表明，ICI-CAT需要存在潜在的肿瘤，并明显增加 ICI处理后发生的肿瘤细胞组织因子（TF）的表达。我们的模型还支持 ICI-Cat中的中性粒细胞外陷阱（网）和血小板激活；还提出了血小板激活通过我们证明了循环血小板中性嗜性骨料的水平升高，接受了ICI治疗的患者。在细胞水平上，抗PD-1抗体刺激中性粒细胞净释放和促血栓性活性，可能在存在亚阈值凝血酶浓度的情况下，还可以增强血小板激活。在此应用程序中，我们建议使用细胞和动物模型来提高我们对ICI-CAT的理解，并扩展这些对ICI治疗前后患者的临床样本进行研究。在AIM 1中，我们将确定不同的ICI和ICI组合对肿瘤小鼠血栓发展的影响，并评估我们的模型使用其他肿瘤类型和小鼠菌株。我们将检查血栓大小和组成，以及通过耗尽T细胞，中性粒细胞，单核细胞或血小板。我们还将进一步定义参与血栓形成活性表达的细胞机制使用来自正常人类供体的分离白细胞，混合白细胞种群和内皮细胞，与细胞因子和ICI一起孵育。在AIM 2中，我们将通过测量的机械标记来扩展这些研究启动ICI之前和之后患者血浆的炎症和血管激活，并通过比较来自ICI治疗的患者的髓样细胞中的促凝基因表达血栓形成。综上所述，这些研究应提供重要的新信息，从而更好了解机制，以及用于预防和治疗ICI-CAT的新方法。