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

摘要 本申请涉及资金机会公告RFA-HL-17-022， NHLBI生物储藏库的科学价值：探索性研究的科学机会（R21）。 异基因造血细胞移植是治疗许多恶性疾病的潜在疗法， 其临床应用受到慢性移植物抗宿主病（cGVHD）的阻碍。的标准治疗 在过去的30年里一直是类固醇，但这种方法是不完全有效的，并与感染有关 和长期毒性风险。通过一项3期多中心随机试验， 血液干细胞（PBSC）与来自无关供体的骨髓（BM），血液和骨髓移植 临床试验网络显示，在PBSC组中，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），而无 急性GVHD或复发发生率的组间差异显著。目前没有 经验证的实验室测试，以分层发展cGVHD的可能性。我们最近报道了一个四- 生物标志物组[肿瘤发生抑制2（ST 2），趋化因子（C-X-C基序）配体9（CXCL 9），基质 金属蛋白酶3（MMP 3）和骨桥蛋白（OPN）]在移植后100天和 cGVHD，区分有和没有cGVHD的患者。在正在进行的实验中，我们还 通过分析cGVHD小鼠蛋白质组发现，鼠CCL 9或人CCL 15的等同物是 在发生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蛋白质生物标志物对未来cGVHD发生的预后价值，以及与cGVHD发生的相关性。 在来自无关供体移植的PBSC与BM中具有cGVHD发生率的候选者。使用这种相同的 患者队列，我们还将寻求确定和验证其他预后生物标志物使用我们的良好， 建立了蛋白质组学工作流程，可在约300份血浆中识别和定量2000多种血浆蛋白 在HCT后+90天，从患有或不患有cGVHD的患者中采集样本，并将这些生物标志物整合到一个 具有cGVHD发生的最大预后潜力的连贯生物标志物组。具体目标1将 验证PBSC中cGVHD发生风险的生物标志物组及其与cGVHD发生率的相关性 与无关供体移植的骨髓进行比较。具体目标2将确定和验证其他 通过我们的蛋白质组学管道，为cGVHD发生风险提供移植特异性生物标志物。如果 如果成功，我们将在多中心研究中定义一个多层生物标志物组用于cGVHD发生的预后。 比较PBSC与BM的前瞻性人群。一旦验证，生物标志物将允许风险分层 对于cGVHD的发生和个性化治疗，如果在治疗过程中早期引入， 移植生物标志物还可以提示cGVHD特异性治疗靶点。

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.