Ustekinumab for Graft versus Host Disease Prevention (IND 144540)

项目摘要 在同种异体造血细胞移植后提供的当前标准免疫抑制（IS）预防 因此，造血干细胞移植（HCT）不能有效地预防HCT后的移植物抗宿主病（GVHD）。重要的是，GVHD 导致HCT相关的发病、死亡和生活质量受损。非亲缘供者HCT的接受者是 特别是考虑到过度GVHD风险，迫切需要针对这些患者的研究策略， needed.我们的实验和临床试验数据支持选择性IL-12/23 p40中和是一种合理的治疗方法。 和靶向的方法来预防GVHD：在小鼠系统中，我们证明了IL-12阻断可以预防GVHD。 GVHD。在最初的概念验证试验临床试验中，我们证明了IL-12/23 p40中和与IL-12/23 p40中和的作用。 药物乌司奴单抗安全地延长了至急性GVHD发作的时间，改善了II-IV级急性无GVHD 存活、Th 1和Th 17细胞应答降低、REG 3a（GVHD致死性的血液生物标志物）降低， 并显著改善总生存率和CRFS（慢性GVHD，无复发生存率）。建筑从 根据这些数据，我们现在提出一项随机、双盲、安慰剂对照的II期试验，以确定 乌司奴单抗治疗vs.安慰剂（均与标准药理学免疫抑制预防性给药） 改善6个月II-IV级急性GVHD无存活率。次要终点将全面评估以下风险/获益： 研究干预、HCT后2年的慢性GVHD结局和患者报告的症状 负担和QOL。我们还将辨别这种干预对HCT后人体免疫的生物学影响 通过全面的研究。总的来说，该提案具有推进以下研究领域的重大潜力： 因此，本发明提供了用于治疗血液恶性肿瘤和病症的安全HCT利用的方法和系统。

PROJECT SUMMARY Current standard immune suppression (IS) prophylaxis delivered after allogeneic hematopoietic cell transplantation (HCT) fails to effectively prevent graft vs. host disease (GVHD) after HCT. Importantly, GVHD leads to HCT-associated morbidity, death, and impaired quality of life. Recipients of unrelated donor HCT are in particular need given excess GVHD risk, and investigational strategies tailored to these patients are urgently needed. Our experimental and clinical trial data support that selective IL-12/23p40 neutralization is a rational and targeted approach to prevent GVHD: In murine systems, we demonstrate that IL-12 blockade prevents GVHD. In an initial proof of concept trial clinical trial, we demonstrated that IL-12/23p40 neutralization with the agent ustekinumab safely prolonged time to acute GVHD onset, improved grade II-IV acute GVHD-free survival, decreased Th1 and Th17 cell responses, decreased REG3a (a blood biomarker of GVHD lethality), and significantly improved overall survival and CRFS (chronic GVHD-, relapse-free survival). Building from these data, we now propose a randomized, double-blinded, placebo-controlled phase II trial to determine if ustekinumab therapy vs. placebo (both given with standard pharmacologic immune suppression prophylaxis) improves 6 month grade II-IV acute GVHD-free survival. Secondary endpoints will fully assess risk/benefit of the study intervention, chronic GVHD outcomes through 2 years post-HCT, and patient-reported symptom burden and QOL. We will also discern the biologic impact of this intervention on human immunity after HCT through comprehensive studies. In total, the proposal has major potential to advance the research field of transplantation, and enhance safe HCT utilization for treatment of hematological malignancies and disorders.