Ustekinumab for Graft versus Host Disease Prevention (IND 144540)

项目总结 目前标准的免疫抑制(IS)预防是在异基因造血细胞之后进行的 移植(HCT)不能有效预防HCT后移植物抗宿主病(GVHD)。重要的是，GVHD 导致与红细胞压积相关的发病率、死亡率和生活质量受损。无血缘关系的供者红细胞移植的受者为 尤其需要考虑到GVHD风险过高，迫切需要针对这些患者量身定做的研究策略 需要的。我们的实验和临床试验数据支持选择性IL-12/23p40中和是合理的 预防GVHD的有针对性的方法：在小鼠系统中，我们证明了IL-12的阻断可以防止 GVHD。在最初的概念验证试验临床试验中，我们证明了IL-12/23p40与 Ustekinumab安全地延长了急性GVHD的发病时间，改善了II-IV级急性GVHD的解除 存活率降低，Th1和Th17细胞反应降低，REG3a(GVHD致死性的血液生物标志物)减少， 显著改善总体存活率和CRF(慢性移植物抗宿主病、无复发存活率)。建筑自 根据这些数据，我们现在建议进行一项随机、双盲、安慰剂对照的II期试验，以确定 Ustekinumab疗法与安慰剂(两者均采用标准的药物免疫抑制预防) 提高6个月II-IV级急性无移植物抗宿主病的存活率。辅助终端将全面评估以下各项的风险/收益 研究干预、HCT后2年慢性GVHD结局和患者报告的症状 负担和生活质量。我们还将了解这种干预对HCT后人类免疫的生物学影响。 通过全面的研究。总体而言，该提案具有推动以下研究领域的重大潜力 移植，提高血细胞移植治疗恶性血液病和疾病的安全性。

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.