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.

摘要