Biomarkers for risk of chronic Graft-Versus-Host Disease occurrence

慢性移植物抗宿主病发生风险的生物标志物

• 批准号: 9433011
• 负责人: Sophie Paczesny
• 金额: $ 13.18万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-12 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9433011
• 关键词: Acute Graft Versus Host Disease; Address; Allogenic; Award; Biological Markers; Biology; Blood; Blood Tests; Bone Marrow; CCL15 gene; CXCL9 gene; Clinical; Clinical Trials; Clinical Trials Network; Complication; Development; Disease; Enzyme-Linked Immunosorbent Assay; Funding Opportunities; Future; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Human; Incidence; Infection; Intervention; Laboratories; Ligands; Malignant - descriptor; Marrow; Measures; Monitor; Mus; National Heart, Lung, and Blood Institute; Outcome; Patients; Performance; Peripheral Blood Stem Cell; Peripheral Stem Cell Transplantation; Phase; Physicians; Plasma; Plasma Proteins; Population; Preventive care; Prognostic Marker; Proteins; Proteome; Proteomics; Regression Analysis; Relapse; Reporting; Research; Risk; Risk stratification; Sampling; Sampling Studies; Source; Steroids; Stromelysin 1; Technology; Testing; Therapeutic; Toxic effect; Transplantation; Tumorigenicity; biobank; biomarker panel; candidate marker; chemokine; chronic graft versus host disease; clinical biomarkers; clinically relevant; cohesion; cohort; curative treatments; experimental study; hematopoietic cell transplantation; high risk; high risk population; innovation; insight; mortality; novel marker; osteopontin; outcome forecast; patient stratification; personalized medicine; prognostic; prognostic value; prospective; protein biomarkers; randomized trial; specific biomarkers; standard care; therapeutic target

ABSTRACT This application addresses the Funding Opportunity Announcement RFA-HL-17-022 for Maximizing the Scientific Value of the NHLBI Biorepository: Scientific Opportunities for Exploratory Research (R21). Allogeneic hematopoietic cell transplantation is a potentially curative therapy for many malignant diseases but its clinical utility has been impeded by chronic graft versus host disease (cGVHD). The standard treatment for the last 30 years has been steroids but this approach is incompletely effective and associated with infections and long-term risks of toxicity. Through a phase 3 multicenter randomized trial of transplantation of peripheral- blood stem cells (PBSC) versus bone marrow (BM) from unrelated donors, the Blood and Marrow Transplant Clinical Trials Network has shown that the incidence of cGVHD at 2 years in the PBSC group was 53% (95% CI, 45 to 61), as compared with 41% (95% CI, 34 to 48) in the BM group (P = 0.01), while there were no significant between-group differences in the incidence of acute GVHD or relapse. Currently there are no validated laboratory tests to stratify for the likelihood of developing cGVHD. We recently reported a four- biomarker panel [Suppression of Tumorigenicity 2 (ST2), chemokine (C-X-C motif) ligand 9 (CXCL9), matrix metalloproteinase 3 (MMP3), and osteopontin (OPN)] measured at 100 days post-transplant and at onset of cGVHD that discriminated between patients with and without cGVHD. In ongoing experiments, we have also found through profiling of a cGVHD mouse proteome that murine CCL9 or equivalent in human to CCL15 was increased in patients who develop cGVHD. During this award period, we propose to explore these candidate cGVHD protein biomarkers for their prognostic value for future cGVHD occurrence, as well as correlate the candidates with cGVHD incidence in PBSC versus BM from unrelated donor transplantations. Using this same cohort of patients, we will also seek to identify and validate additional prognostic biomarkers using our well- established proteomic workflow that can identify and quantify more than 2000 plasma proteins in ~300 plasma samples from patients with or without cGVHD at day +90 post-HCT and integrate these biomarkers into a cohesive biomarker panel with the greatest prognostic potential for cGVHD occurrence. Specific Aim 1 will validate a biomarker panel for risk of cGVHD occurrence and its correlation with cGVHD incidence in PBSC versus BM from unrelated donor transplantations. Specific Aim 2 will identify and validate additional transplantation-specific biomarkers for risk of cGVHD occurrence through our proteomics pipeline. If successful, we will define a multilayer biomarker panel for prognosis of cGVHD occurrence in a multicenter prospective population comparing PBSC versus BM. Once validated the biomarkers will allow risk-stratification for cGVHD occurrence and personalized therapies that will be more efficient if introduced early in the course of transplant. The biomarkers may also suggest cGVHD-specific therapeutic targets.

抽象的 此申请针对资助机会公告 RFA-HL-17-022，以最大限度地提高 NHLBI 生物样本库的科学价值：探索性研究的科学机会 (R21)。 异基因造血细胞移植是许多恶性疾病的潜在治疗方法，但 其临床应用受到慢性移植物抗宿主病（cGVHD）的阻碍。标准治疗方法为 过去30年一直使用类固醇，但这种方法并不完全有效，并且与感染有关 和长期毒性风险。通过外周血移植的 3 期多中心随机试验 血液干细胞 (PBSC) 与来自无关捐赠者的骨髓 (BM)，血液和骨髓移植 临床试验网络显示，PBSC 组 2 年时 cGVHD 的发生率为 53%（95% CI，45 至 61），而 BM 组为 41%（95% CI，34 至 48）（P = 0.01），而没有 急性 GVHD 或复发的发生率存在显着组间差异。目前没有 经验证的实验室测试对发生 cGVHD 的可能性进行分层。我们最近报道了四项 生物标志物组 [致瘤性抑制 2 (ST2)、趋化因子（C-X-C 基序）配体 9 (CXCL9)、基质 金属蛋白酶 3 (MMP3) 和骨桥蛋白 (OPN)] 在移植后 100 天和移植开始时进行测量 cGVHD 区分患有和不患有 cGVHD 的患者。在正在进行的实验中，我们还 通过对 cGVHD 小鼠蛋白质组的分析发现，小鼠 CCL9 或人类 CCL15 的等效物 发生 cGVHD 的患者中增加。在此奖励期间，我们建议探索这些候选人 cGVHD 蛋白生物标志物对未来 cGVHD 发生的预后价值，以及与 PBSC 与无关供体移植的 BM 中 cGVHD 发生率的候选者。使用同样的 对于患者队列，我们​​还将寻求使用我们良好的方法来识别和验证其他预后生物标志物 建立了蛋白质组工作流程，可以识别和定量约 300 种血浆中的 2000 多种血浆蛋白 HCT 后第 +90 天取自患有或不患有 cGVHD 的患者样本，并将这些生物标志物整合到 对 cGVHD 发生具有最大预后潜力的粘性生物标志物组。具体目标 1 将 验证生物标志物组的 cGVHD 发生风险及其与 PBSC 中 cGVHD 发生率的相关性 与来自无关供体移植的 BM 比较。具体目标 2 将确定并验证额外的 通过我们的蛋白质组学管道确定 cGVHD 发生风险的移植特异性生物标志物。如果 如果成功的话，我们将定义一个多层生物标志物组，用于多中心 cGVHD 发生的预后 比较 PBSC 与 BM 的前瞻性人群。一旦经过验证，生物标志物将允许风险分层 针对 cGVHD 的发生和个性化治疗，如果在病程早期引入，将会更加有效 移植。生物标志物还可能提示 cGVHD 特异性治疗靶点。