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: 10084808
• 负责人: Iwijn De Vlaminck
• 金额: $ 73.37万
• 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/10084808
• 关键词: ART protein; 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; Lead; Life; Liver; Malignant - descriptor; Maps; Measurement; Medical; Metagenomics; Methods; Methylation; Modality; Monitor; Non-Invasive Cancer 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; Savings; 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; 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.

异基因造血细胞移植（HCT）是一种广泛用于治疗各种恶性和非恶性肿瘤的方法。 非恶性血液病每年有超过8,500名患者在美国接受HCT移植。 然而，高达50%的患者在移植后的第一年因移植物抗宿主病（GVHD）而发生并发症。 HCT。当供体免疫细胞攻击患者自身组织时，发生GVHD。GVHD可以在任何地方发生， 皮肤、肠道和肝脏最常受到影响。移植物抗宿主病仍然是一个更广泛的主要障碍之一， 同种异体HCT的应用。 aGVHD的早期诊断对于指导治疗决策和预防严重器官损伤和死亡至关重要。 不幸的是，很少有信息的诊断方法。在目前的临床实践中， aGVHD几乎完全依赖于临床症状的存在，并需要通过侵入性活检进行确认 例如皮肤活检、结肠镜检查、上消化道内窥镜检查或肝活检。HCT患者迫切需要 更好的选择。 该提案的目标是开发和应用血液检测来检测急性GVHD（aGVHD）， 预测长期HCT结果。该检测采用全基因组范围的甲基化标记分析， 在血液中的循环无细胞DNA（cfDNA）内，以追踪它们的来源组织，并定量组织特异性 HCT后损伤。这一概念得到了大量试点数据的支持。 我们将进行cfDNA对患有单器官aGVHD的HCT受者分层的效用的回顾性研究。 (Aim 1），以及cfDNA用于检测GVHD的早期发作和预测HCT的效用的前瞻性研究 风险（目标2）。这些目标共同探讨了高度创新的概念，即测量组织的 cfDNA在血浆中的来源使得能够i）检测aGVHD，ii）定量aGVHD的严重性并确定其器官功能。 iii）预测HCT后死亡率，和iv）预测aGVHD治疗的结果。 该提案直接解决了一个迫切的、未得到满足的医疗需求：aGVHD的早期和非侵入性诊断 HCT后因此，这些研究具有高度的转化性。一种信息量大的非侵入性监测工具， 为新的治疗方式和移植策略提供信息。认识到通用预防性药物的局限性 在针对aGVHD的治疗中，cfDNA测定可以在指导先发制人的治疗策略中找到未来的用途，从而 减少了移植后延长免疫抑制治疗的需要。此外，早期检测 aGVHD可缩短治疗性免疫抑制的持续时间并改善患者结局。