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

描述（由申请人提供）：同种异体造血干细胞移植（HSTC）后的急性移植物抗宿主病（GVHD）发病率（高达50%）和相关死亡率（高达50%）之间存在根本差距，并且缺乏治疗和生物相关研究。这一空白代表了一个重要的问题，因为直到它被填补，治疗将仅限于非特异性类固醇靶向效应细胞。我们的长期目标是识别和验证具有风险分层和治疗靶向潜力的GVHD生物标志物。我们在这项应用中的目标是研究对GVHD治疗反应性的早期生物标志物，这些生物标志物是药物可靶向的，也可以预测GVHD的发生。我们的中心假设是：(1)血浆生物标志物组，包括抑制致瘤性2 (ST2)，预测对GVHD治疗的反应性和生存，(2)ST2，主要候选物，也可以在临床症状出现之前预测GVHD， (3) ST2可以用抗体靶向来缓解GVHD， (4) ST2/IL33途径在GVHD的病理中很重要。这一假设是基于我们的初步数据形成的(i)表征了9个生物标志物的小组，这些生物标志物在治疗开始时测量时可以预测治疗后28天的反应和治疗后180天的生存，（ii）显示在hsct后14天测量的ST2可以预测100天的GVHD， （iii）显示小鼠抗ST2嵌合抗体可以预防GVHD辐照小鼠模型中的GVHD。（iv）显示在存在IL33的情况下，人类CD4+ Th2分化在存在ST2的情况下下降，但在使用人类抗ST2中和抗体治疗后恢复。这项研究的基本原理是，一旦我们能够确定对传统治疗无效的患者，以及随后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，如果早期引入和有针对性，这是最有效的。该假设将通过三个具体目标进行验证：1)测试ST2和其他可靶向药物的候选生物标志物，以预测GVHD治疗前患者样本中对GVHD治疗的反应性。2)在移植后早期检测ST2和其他可靶向药物的候选生物标志物，以预测急性GVHD的发生和6个月非复发死亡率。3)确定抑制ST2与IL33（其唯一已知的配体）相互作用的效果，作为药物靶向GVHD生物标志物的原理证明。这项研究具有重要意义，因为在症状发作时识别抗药GVHD生物标志物组有望增强我们在开始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发展之前，在移植过程的早期识别GVHD高风险患者的能力将允许先发制人的干预。最终，这项研究可能会导致发现一种gvhd特异性药物，该药物将针对适当的效应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.