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

描述（由申请人提供）：在异基因造血干细胞移植（HSTC）后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，并且缺乏治疗和生物学相关研究。这个缺口代表了一个重要的问题，因为在它被填补之前，治疗将限于效应细胞的非特异性类固醇靶向。我们的长期目标是确定和验证GVHD的生物标志物的潜在风险分层和治疗靶向。我们在本申请中的目标是研究对GVHD治疗反应性的药物靶向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，包括致瘤性抑制2（ST 2），预测对GVHD治疗的响应性和存活，（ii）ST 2，主要候选物，也可以在临床体征出现之前预测GVHD，（iii）ST 2可以用抗体靶向以减轻GVHD，和（iv）ST 2/IL 33途径在GVHD的病理学中是重要的。该假设是基于我们的初步数据形成的：（i）表征了一组九种生物标志物，当在治疗开始时测量时，所述生物标志物预测治疗后第28天的应答和第180天的存活，（ii）显示在HSCT后第14天测量的ST 2预测到第100天的GVHD，（iii）显示鼠抗ST 2嵌合抗体预防GVHD的辐射小鼠模型中的GVHD，和（iv）显示在IL 33存在下的人CD 4 + Th 2分化在ST 2存在下降低，但在用人抗ST 2中和Ab处理后恢复。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的患者，以及随后发病率和死亡率风险特别高的患者，我们就可以提出个性化的治疗计划，如果早期和有针对性地引入，这些计划是最有效的。将以三个具体目的检验该假设：1）检验ST 2和其他药物可靶向的候选生物标志物，用于预测来自两个独立组的GVHD治疗前患者样品中对GVHD治疗的响应性。2)测试ST 2和其他药物靶向候选生物标志物，用于预测移植后早期测试时的急性GVHD发生率和6个月非复发死亡率。3)确定抑制ST 2和IL 33（其唯一已知的配体）之间的相互作用的效果，作为药物靶向GVHD生物标志物的原理证明。拟议的研究是重要的，因为在症状发作时识别治疗抗性GVHD生物标志物面板预计将增强我们在开始GVHD治疗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。在移植过程早期，在GVHD发展之前识别GVHD高危患者的能力将允许先发制人的干预。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，以提高疗效和降低毒性。

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.