Translating Novel Drug-Targetable Biomarkers to Treat Graft versus Host Disease

转化新型药物靶向生物标志物来治疗移植物抗宿主病

• 批准号: 8841692
• 负责人: Sophie Paczesny
• 金额: $ 32.56万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-03 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8841692
• 关键词: Acute Graft Versus Host Disease; Affect; Aftercare; Allogenic; Antibodies; Biological Markers; Biological Response Modifier Therapy; Biology; Cancer Center; Cancer Patient; Clinical; Complication; Correlative Study; Data; Development; Diagnostic; Diagnostic tests; Drug Targeting; Effector Cell; Enzyme-Linked Immunosorbent Assay; Equilibrium; Goals; Health; Hematological Disease; Hematopoietic Stem Cell Transplantation; Human; Immunotherapeutic agent; Individual; Institutes; Intervention; Lead; Life; Ligands; Measures; Michigan; Morbidity - disease rate; Mus; Outcome; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Pilot Projects; Plasma; Proteins; Proteomics; Research; Risk; Role; Safety; Sampling; Steroid therapy; Steroids; Stratification; Symptoms; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Therapeutic immunosuppression; Toxic effect; Translating; Transplantation; Tumorigenicity; Universities; Validation; Work; base; cancer therapy; chimeric antibody; clinically relevant; graft vs host disease; high risk; improved; insight; mortality; mouse model; neutralizing antibody; new therapeutic target; novel; novel therapeutics; personalized medicine; prevent; prognostic value; response; tandem mass spectrometry; therapeutic target; therapy resistant; treatment duration; treatment planning

DESCRIPTION (provided by applicant): A fundamental gap exists between acute graft-versus-host disease (GVHD) rates (up to 50%) and the related mortality (up to 50%) following allogeneic hematopoietic stem cell transplantation (HSTC) and the paucity of therapies and biological correlative studies offered. This gap represents an important problem, because until it is filled, therapies will be limited to the nonspecific steroidal targeting of effector cells. Our ong-term goal is to identify and validate GVHD biomarkers with the potential for risk stratification an therapeutic targeting. Our objective in this application is to investigate early biomarkers of responsiveness to GVHD therapy that are drug targetable as well as biomarkers that can predict occurrence of GVHD. Our central hypothesis is that (i) a plasma biomarker panel, including suppression of tumorigenicity 2 (ST2), predicts responsiveness to GVHD therapy and survival, (ii) ST2, the lead candidate, can also predict GVHD before the clinical signs appear, (iii) ST2 can be targeted with antibodies to alleviate GVHD, and (iv) that the ST2/IL33 pathway is important in the pathology of GVHD. This hypothesis was formed based on our preliminary data (i) characterizing a panel of nine biomarkers that predict the day 28 response and the day 180 post-treatment survival when measured at initiation of therapy, (ii) showing that ST2 measured at day 14 post-HSCT predicts GVHD by day 100, (iii) showing that the murine anti-ST2 chimeric antibody prevents GVHD in an irradiated mouse model of GVHD, and (iv) showing that human CD4+ Th2 differentiation in the presence of IL33 is decreased in the presence of ST2 but is restored following treatment with human anti-ST2 neutralizing Ab. The rationale for this study is that once we are able to identify patients who will not respond to traditional treatments and who are at particularly high risk for subsequent morbidity and mortality, we can propose personalized treatment plans that are most effective if introduced early and targeted. This hypothesis will be tested with three specific aims: 1) Test ST2 and other drug-targetable candidate biomarkers for prediction of responsiveness to GVHD treatment in GVHD pre-treatment patient samples from two independent sets. 2) Test ST2 and other drug-targetable candidate biomarkers for prediction of acute GVHD occurrence and 6 month non-relapse mortality when tested early post-transplant. 3) Determine the effect of inhibiting the interaction between ST2 and IL33, its only known ligand, as proof-of-principle of a drug targetable GVHD biomarker. The proposed research is significant because the identification of therapy-resistant GVHD biomarker panels at symptom onset is expected to enhance our ability to risk-stratify patients before initiating GVHD treatment, and will guide the intensity and duration of treatment. The ability to identify patientsat high risk for GVHD early in their transplant course before GVHD development will allow for preemptive interventions. Ultimately, the proposed research may result in the discovery of a GVHD-specific drug, which will target the appropriate effector T cells to increase efficacy and lower toxicity.

描述（由申请人提供）：在同种异体造血干细胞移植（HSTC）之后，急性移植物抗宿主病（GVHD）疾病（GVHD）率（GVHD）率（GVHD）率（最高50％）（最高50％）之间存在基本差距。该差距代表了一个重要的问题，因为在填充疗法之前，疗法将仅限于效应细胞的非特异性类固醇靶向。我们的ONG期限目标是识别和验证GVHD生物标志物，并具有将治疗靶向靶向的风险分层的潜力。我们在本应用中的目标是研究对GVHD疗法的反应性的早期生物标志物，这些疗法是可针对药物的，以及可以预测GVHD发生的生物标志物。我们的中心假设是（i）血浆生物标志物小组（包括抑制肿瘤性2（ST2））预测对GVHD治疗和生存的反应性，（II）ST2（ii）首席候选人，也可以预测GVHD，也可以在临床症状出现之前（III）parties the the ponteries the Antibodies/partibiation the -GVHD（iii）the 2 and。在GVHD的病理学中很重要。 This hypothesis was formed based on our preliminary data (i) characterizing a panel of nine biomarkers that predict the day 28 response and the day 180 post-treatment survival when measured at initiation of therapy, (ii) showing that ST2 measured at day 14 post-HSCT predicts GVHD by day 100, (iii) showing that the murine anti-ST2 chimeric antibody prevents GVHD in an irradiated mouse model of GVHD和（iv）表明在存在IL33的存在下人类CD4+ Th2分化在ST2存在下降低，但在用人类抗ST2中和AB进行处理后，正在恢复。这项研究的理由是，一旦我们能够识别出对传统治疗的反应，并且随后发病率和死亡率的风险特别高的患者，我们就可以提出个性化的治疗计划，如果提早引入并有针对性，这是最有效的。该假设将以三个特定目的进行检验：1）测试ST2和其他可靶向药物的候选生物标志物，以预测GVHD预处理前患者样本中对GVHD治疗的响应能力的预测。 2）测试急性GVHD发生的测试ST2和其他可靶向药物的候选生物标志物，并在移植后早期测试时进行了6个月的非释放死亡率。 3）确定抑制ST2和IL33之间的相互作用的效果（其唯一已知的配体）是药物靶向GVHD生物标志物的原则证明。拟议的研究很重要，因为症状发作时耐药的GVHD生物标志物面板的鉴定有望增强我们在启动GVHD治疗之前对患者进行风险分层的能力，并将指导治疗的强度和持续时间。在GVHD开发之前，在移植课程早期识别GVHD的高风险的能力将允许进行先发制人的干预措施。最终，拟议的研究可能导致发现GVHD特异性药物，该药物将针对适当的效应T细胞以提高功效并降低毒性。