Biomarkers for risk of chronic Graft-Versus-Host Disease occurrence
Biomarkers for risk of chronic Graft-Versus-Host Disease occurrence
批准号:
9433011
负责人:
Sophie Paczesny
金额:
$13.18万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-09-12 至 2019-08-31
关键词:
Acute Graft Versus Host DiseaseAddressAllogenicAwardBiological MarkersBiologyBloodBlood TestsBone MarrowCCL15 geneCXCL9 geneClinicalClinical TrialsClinical Trials NetworkComplicationDevelopmentDiseaseEnzyme-Linked Immunosorbent AssayFunding OpportunitiesFutureHematologic NeoplasmsHematopoietic Stem Cell TransplantationHumanIncidenceInfectionInterventionLaboratoriesLigandsMalignant - descriptorMarrowMeasuresMonitorMusNational Heart, Lung, and Blood InstituteOutcomePatientsPerformancePeripheral Blood Stem CellPeripheral Stem Cell TransplantationPhasePhysiciansPlasmaPlasma ProteinsPopulationPreventive carePrognostic MarkerProteinsProteomeProteomicsRegression AnalysisRelapseReportingResearchRiskRisk stratificationSamplingSampling StudiesSourceSteroidsStromelysin 1TechnologyTestingTherapeuticToxic effectTransplantationTumorigenicitybiobankbiomarker panelcandidate markerchemokinechronic graft versus host diseaseclinical biomarkersclinically relevantcohesioncohortcurative treatmentsexperimental studyhematopoietic cell transplantationhigh riskhigh risk populationinnovationinsightmortalitynovel markerosteopontinoutcome forecastpatient stratificationpersonalized medicineprognosticprognostic valueprospectiveprotein biomarkersrandomized trialspecific biomarkersstandard caretherapeutic target
中文摘要
摘要
本申请涉及资金机会公告RFA-HL-17-022,旨在最大限度地
NHLBI生物库的科学价值:探索性研究的科学机会(R21)。
异基因造血细胞移植是一种治疗许多恶性疾病的潜在疗法,但
慢性移植物抗宿主病(CGVHD)阻碍了其临床应用。标准的治疗方法
过去30年一直在服用类固醇,但这种方法并不完全有效,而且与感染有关。
以及长期的毒性风险。通过外周血淋巴细胞移植的3期多中心随机试验
血液干细胞(PBSC)与非血缘关系供者骨髓(BM)的比较--血液和骨髓移植
临床试验网络显示,PBSC组2年内cGVHD的发生率为53%(95%
CI,45~61),而BM组为41%(95%CI,34~48)(P=0.01),而无
急性移植物抗宿主病或复发的发生率在组间有显著差异。目前没有
经过验证的实验室测试,以分层的可能性发展为cGVHD。我们最近报告了一起四起-
生物标志物小组[抑制致瘤性2(ST2),趋化因子(C-X-C基序)配体9(CXCL9),基质
在移植后100天和移植开始时检测金属蛋白酶3(MMP3)和骨桥蛋白(OPN)。
CGVHD区分有无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或其在人类中的等价物是CCL15
在发展为cGVHD的患者中增加。在本次颁奖期间,我们建议探索这些候选人
CGVHD蛋白生物标记物对未来cGVHD发生的预后价值,以及与
外周血干细胞中cGVHD发生率与非血缘关系供者骨髓中cGVHD发生率比较。使用相同的
我们还将使用我们的Well-Well来识别和验证其他预后生物标志物-
建立了蛋白质组学工作流程,可以在~300血浆中鉴定和定量2000多种血浆蛋白质
在HCT后+90天有或没有cGVHD患者的样本,并将这些生物标记物整合到
对cGVHD发生有最大预测潜力的凝聚力生物标志物小组。具体目标1将
验证生物标志物小组在外周干细胞中发生cGVHD的风险及其与cGVHD发生率的相关性
与无血缘关系的供者移植的骨髓相比。特定目标2将确定和验证其他
通过我们的蛋白质组学渠道预测发生cGVHD风险的移植特异性生物标记物。如果
成功,我们将定义一个多层生物标志物小组,用于预测多中心发生cGVHD的预后
PBSC与BM的预期人群比较。一旦得到验证,生物标志物将允许进行风险分层
对于cGVHD的发生和个性化治疗,如果在早期引入将会更有效
移植。这些生物标记物也可能提示cGVHD的特异性治疗靶点。
英文摘要
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.
期刊论文(0)
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科研奖励(0)
会议论文
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