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

基本信息

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
项目类别：
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

项目摘要

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）：同种异体造血干细胞移植（HSTC）和移植后的急性移植物抗宿主病（GVHD）发生率（高达 50%）和相关死亡率（高达 50%）之间存在根本性差距。缺乏提供的治疗方法和生物学相关研究。这个缺口代表了一个重要的问题，因为在它被填补之前，治疗将仅限于效应细胞的非特异性类固醇靶向。我们的长期目标是识别和验证具有风险分层和治疗目标潜力的 GVHD 生物标志物。我们在此应用中的目的是研究可药物靶向的 GVHD 治疗反应的早期生物标志物以及可以预测 GVHD 发生的生物标志物。我们的中心假设是 (i) 血浆生物标志物组，包括抑制致瘤性 2 (ST2)，可以预测对 GVHD 治疗的反应和生存，(ii) ST2 作为主要候选者，也可以在临床症状出现之前预测 GVHD，（ iii) ST2 可以用抗体靶向来减轻 GVHD，并且 (iv) ST2/IL33 途径在 GVHD 的病理学中很重要。这一假设是基于我们的初步数据形成的：(i) 表征一组九种生物标志物，这些生物标志物在治疗开始时测量，可预测治疗后第 28 天的反应和治疗后第 180 天的生存率，(ii) 显示在治疗后第 14 天测量的 ST2 -HSCT 在第 100 天预测 GVHD，(iii) 显示鼠抗 ST2 嵌合抗体可预防受辐射的 GVHD 小鼠模型中的 GVHD，以及 (iv) 显示人类IL33 存在下的 CD4+ Th2 分化在 ST2 存在下降低，但在用人抗 ST2 中和抗体治疗后恢复。这项研究的基本原理是，一旦我们能够识别出对传统治疗没有反应以及后续发病和死亡风险特别高的患者，我们就可以提出个性化的治疗计划，如果尽早引入并有针对性，这些计划将是最有效的。该假设将通过三个具体目标进行测试：1）测试 ST2 和其他药物靶向候选生物标志物，用于预测来自两个独立组的 GVHD 治疗前患者样本对 GVHD 治疗的反应。 2) 测试 ST2 和其他药物靶向候选生物标志物，以预测移植后早期测试时的急性 GVHD 发生和 6 个月非复发死亡率。 3) 确定抑制 ST2 和 IL33（其唯一已知配体）之间相互作用的效果，作为药物靶向 GVHD 生物标志物的原理证明。拟议的研究意义重大，因为在症状出现时识别治疗耐药的 GVHD 生物标志物组预计将增强我们在开始 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 发生之前的移植过程中早期识别 GVHD 高风险患者的能力将允许采取先发制人的干预措施。最终，拟议的研究可能会发现一种 GVHD 特异性药物，该药物将靶向适当的效应 T 细胞以提高疗效并降低毒性。