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

描述(由申请人提供)：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%)之间存在根本差距，以及所提供的治疗和生物学相关研究的匮乏。这一缺口代表着一个重要的问题，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GVHD生物标记物具有作为治疗靶点的风险分层的可能性。我们在这项应用中的目标是研究GVHD治疗的早期生物标记物，这些标记物是药物靶向的，以及可以预测GVHD发生的生物标记物。我们的中心假设是：(I)血浆生物标志物组合，包括致瘤性抑制2(ST2)，预测GVHD治疗的反应性和存活率，(Ii)ST2，领先候选者，也可以在临床症状出现之前预测GVHD，(Iii)ST2可以被抗体靶向以减轻GVHD，以及(Iv)ST2/IL33通路在GVHD的病理中很重要。这一假说是基于我们的初步数据(I)鉴定了一组预测第28天反应和第180天治疗后存活的9个生物标志物的特征，(Ii)显示在HSCT后第14天测量的ST2可预测到100天GVHD，(Iii)表明小鼠抗ST2嵌合抗体可防止GVHD在受辐射的小鼠模型中发生GVHD，(Iv)显示在IL33存在的情况下，人CD4+Th2的分化在ST2存在的情况下会减少，但在用人抗ST2中和抗体治疗后可恢复。这项研究的基本原理是，一旦我们能够确定哪些患者对传统治疗没有反应，以及哪些患者随后的发病率和死亡率特别高，我们就可以提出个性化的治疗计划，如果及早推出和有针对性的话，这些计划是最有效的。这一假设将以三个具体目标进行验证：1)测试ST2和其他药物靶向候选生物标记物，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)在移植后早期检测ST2和其他药物靶向候选生物标志物，以预测急性移植物抗宿主病的发生和6个月无复发死亡率。3)确定抑制ST2与其已知的唯一配体IL33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。这项拟议的研究具有重要意义，因为在症状开始时识别治疗耐药的GVHD生物标志物小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发生之前，能够在移植过程的早期识别出GVHD的高危患者，这将允许先发制人的干预。最终，这项拟议的研究可能会发现一种针对GVHD的特异性药物，该药物将靶向适当的效应T细胞，以提高疗效并降低毒性。

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.