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展之一，并且迅速发展转向许多癌症的一线治疗。癌症免疫治疗的机制是使正常的通过施用单克隆免疫检查点抑制剂 (ICI) 来调节免疫调节途径针对关键免疫调节蛋白（包括 PD-1、PD-L1 和 CTLA-4）的抗体。禁用这些途径增强抗肿瘤免疫力。然而，由于这些反应不是肿瘤特异性的，因此 ICI 是与多种免疫相关不良事件 (irAE) 相关。我们和其他人最近报告了 ICI治疗患者血栓形成率高，可能超过20%；鉴于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-癌症相关血栓形成 (ICI-CAT) 已成为一个主要的临床问题，需要更好地了解这种疾病急需。然而，关于 ICI-CAT 机制的信息很少，并且有没有发表的研究讨论这个问题。我们假设 ICI-CAT 是 ICI 诱导的 irAE 潜在肿瘤相关炎症中的细胞激活和促血栓活性。我们的小鼠模型表明 ICI-CAT 需要存在潜在肿瘤，并且显着增加 ICI 治疗后肿瘤细胞组织因子 (TF) 的表达。我们的模型还支持以下角色： ICI-CAT 中的中性粒细胞胞外陷阱 (NET) 和血小板激活；血小板活化也被建议在我们证明循环血小板-中性粒细胞聚集水平升高，接受 ICI 治疗的患者。在细胞水平上，抗 PD-1 抗体刺激中性粒细胞 NET 释放和促血栓形成活性，并可能在凝血酶浓度低于阈值的情况下也能增强血小板活化。在这个应用程序中，我们建议使用细胞和动物模型来增进我们对 ICI-CAT 的理解，并扩展这些对开始 ICI 治疗之前和之后患者的临床样本进行研究。在目标 1 中，我们将确定不同ICI和ICI组合对荷瘤小鼠血栓形成的影响，并评估我们的模型使用其他肿瘤类型和小鼠品系。我们将检查血栓的大小和成分，并且通过消耗小鼠的 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前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、混合白细胞群和内皮细胞，与细胞因子和 ICI 一起孵育。在目标 2 中，我们将通过测量机械标记来扩展这些研究启动 ICI 之前和之后患者血浆中的炎症和血管活化，并通过比较接受 ICI 治疗的患者骨髓细胞中促凝血基因的表达血栓形成。总的来说，这些研究应该提供重要的新信息，从而更好地了解预防和治疗 ICI-CAT 的机制和潜在的新方法。