Epigenetic Profiling of circulating cell-free DNA for the Monitoring of Graft-Versus-Host Disease after Hematopoietic Cell Transplantation

循环游离 DNA 表观遗传分析用于监测造血细胞移植后移植物抗宿主病

• 批准号: 10533829
• 负责人: Iwijn De Vlaminck
• 金额: $ 65.37万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-13 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533829
• 关键词: Acute; Acute Graft Versus Host Disease; Address; Affect; Allogenic; Bacterial Infections; Behavior Therapy; Bioinformatics; Biological Assay; Biopsy; Blood; Blood Circulation; Blood Tests; Caring; Cell Death; Cells; Cessation of life; Clinical; Collaborations; Colonoscopy; Control Groups; DNA sequencing; Data; Detection; Diagnosis; Diagnostic; Early Diagnosis; Endoscopy; Engraftment; Etiology; Future; Genetic Fingerprintings; Goals; Hematological Disease; Hematopoietic Neoplasms; Immune; Immune System Diseases; Immune response; Injury; Life; Liver; Malignant - descriptor; Maps; Measurement; Medical; Metagenomics; Methods; Methylation; Modality; Monitor; Non-Invasive Detection; Non-Malignant; Organ; Outcome; Patient Monitoring; Patient-Focused Outcomes; Patients; Performance; Pilot Projects; Plasma; Procedures; Prospective Studies; Prospective cohort; Proteins; Public Health; Retrospective Studies; Risk; Sampling; Severities; Skin; Symptoms; Testing; Therapeutic immunosuppression; Time; Tissues; Translations; Transplant Recipients; Transplantation; Virus Diseases; accurate diagnosis; biobank; biomarker panel; bisulfite sequencing; blood treatment; cell free DNA; cell type; classification algorithm; clinical practice; cohort; diagnostic strategy; diagnostic tool; early onset; epigenetic profiling; genome-wide; graft vs host disease; hematopoietic cell transplantation; improved; innovation; liver biopsy; mortality; non-invasive monitor; noninvasive diagnosis; organ injury; outcome prediction; prevent; prognostic performance; prophylactic; protein biomarkers; recruit; tool; translational study; treatment strategy

Allogeneic Hematopoietic Cell Transplantation (HCT) is a widely used therapy for a variety of malignant and nonmalignant hematologic diseases. More than 8,500 patients, receive HCT transplants in the US each year. Yet, up to 50% of patients suffer complications due to graft-versus-host disease (GVHD) in the first year after HCT. GVHD occurs when donor immune cells attack the patient’s own tissues. GVHD can occur anywhere, with the skin, gut and liver most frequently affected. GVHD remains one of the major barriers to a more widespread application of allogeneic HCT. Early diagnosis of aGVHD is critical to inform treatment decisions and prevent serious organ injury and death. Unfortunately, few informative diagnostic approaches are available. In current clinical practice, diagnosis of aGVHD relies almost entirely on the presence of clinical symptoms and requires confirmation via invasive biopsy procedures, such as skin biopsy, colonoscopy, upper endoscopy or liver biopsy. HCT patients urgently need a better alternative. The goal of this proposal is to develop and apply a blood test to detect acute GVHD (aGVHD) and to predict long-term HCT outcomes. This test employs genome-wide profiling of methylation marks comprised within circulating cell-free DNA (cfDNA) in blood to trace their tissues-of-origin, and to quantify tissue-specific injury after HCT. This concept is supported by significant pilot data. We will perform a retrospective study of the utility of cfDNA to stratify HCT recipients with single organ aGVHD (Aim 1), and a prospective study of the utility of cfDNA to detect the early onset of GVHD and to predict HCT risk (Aim 2). Together these aims explore the highly innovative concept that a measurement of the tissues-of- origin of cfDNA in plasma enables to i) detect aGVHD, ii) quantify the severity of aGVHD and determine its organ involvement, iii) predict post-HCT mortality, and iv) predict the outcome of aGVHD treatments. This proposal directly addresses an urgent, unmet medical need: the early and noninvasive diagnosis of aGVHD after HCT. These studies are therefore highly translational. A highly informative, noninvasive monitoring tool may inform new treatment modalities and transplant strategies. Recognizing the limitations of universal prophylactic therapy against aGVHD, cfDNA assays could find future use in guiding pre-emptive treatment strategies, thereby reducing the need for prolonged immunosuppressive therapy after transplant. Furthermore, earlier detection of aGVHD could lead to shorter durations of therapeutic immunosuppression and improved patient outcomes.

同种异体造血细胞移植（HCT）是一种广泛使用的疗法，用于多种恶性和 非恶性血液学疾病。每年有8500多名患者在美国接受HCT移植。 然而，多达50％的患者因接枝抗宿主病（GVHD）而遭受并发症 HCT。当供体免疫细胞攻击患者自己的组织时，就会发生GVHD。 GVHD可以发生在任何地方， 皮肤，肠道和肝脏最常受到影响。 GVHD仍然是宽度更高的主要障碍之一 同种异体HCT的应用。 AGVHD的早期诊断对于为治疗决策提供信息至关重要，防止严重的器官损伤和死亡。 不幸的是，很少有信息的诊断方法。在当前的临床实践中 AGVHD几乎完全依赖临床症状的存在，需要通过侵入性活检确认 手术，例如皮肤活检，结肠镜检查，上内窥镜检查或肝活检。 HCT患者迫切需要 更好的选择。 该提案的目的是开发和应用血液检查以检测急性GVHD（AGVHD）和到 预测长期的HCT结果。该测试员工全基因组的甲基化标记分析已完成 在血液中循环无细胞的DNA（CFDNA）中，以追踪其原始时间，并定量组织特异性 HCT后受伤。这个概念得到了重要的试点数据的支持。 我们将对CFDNA实用程序进行回顾性研究，以对单器官AGVHD进行对HCT受体进行分层 （AIM 1），以及对CFDNA效用的前瞻性研究，以检测GVHD的早期发作并预测HCT 风险（目标2）。这些目标共同探讨了高度创新的概念，即对组织的测量 等离子体中cfDNA的起源使i）检测AGVHD，ii）量化AGVHD的严重程度并确定其器官 参与，iii）预测HCT后死亡率，iv）预测AGVHD治疗的结果。 该提案直接解决了紧急，未满足的医疗需求：AGVHD的早期和无创诊断 HCT之后。因此，这些研究被高度翻译。一个信息丰富的无创监测工具可能 告知新的治疗方式和移植策略。识别通用预防的局限性 针对AGVHD的治疗，CFDNA测定法可以在指导先发制人的治疗策略中找到未来的用途 减少了移植后长期免疫抑制治疗的需求。此外，早期发现 AGVHD可能导致热免疫抑制的持续时间较短，并改善了患者预后。