Novel Biologic Therapies for GVHD

移植物抗宿主病的新生物疗法 摘要： 对于高危恶性和非恶性血液病患者，造血干细胞移植 (HCT)通常是治愈的唯一选择。然而，HCT充满了并发症，导致了很高的 毒性和病人死亡。早期无复发死亡的主要原因是急性移植物抗宿主病。 (AGVHD)，死于感染紧随其后。这两者是相互关联的，因为加强全球免疫 抑制以控制AGVHD会增加感染风险。此外，增强的免疫抑制也可以增加 恶性复发的风险。为了推动这一领域向前发展，我们必须制定有针对性的、以证据为基础的预防和 治疗策略，旨在特别控制同种异体反应，同时保持抗肿瘤和抗病毒保护 豁免权。也许对这些靶向疗法的最大需求是GI AGVHD，这是AGVHD的主要原因- 相关死亡。严重阻碍进展的两个问题：(1)我们没有充分认识到 控制胃肠道T细胞渗透与组织滞留或损伤的不同机制 开发特定的疗法。(2)激素难治性GI AGVHD的发病机制尚不清楚。 大大减缓了这种最致命类型的AGVHD的治疗开发。这项提议的目标是 解决这些未得到满足的需求，从而发现GI AGVHD的下一代疗法。 我们将通过完成以下三个具体目标来实现这一目标：(1)确定和验证面向下一代GI的优先顺序 治疗与一种新的转译管道。我们将检验从患者/NHP派生的管道的假设 治疗候选→小鼠→NHP AGVHD模型可以优先考虑新的AGVHD疗法。(2)确定 Notch配体阻断对NHP和移植患者血液和胃肠道免疫状况的影响。我们将测试 假设Notch配体与抗DLL4单抗REGN421一起阻断对GI AGVHD具有保护作用，并且它 这是通过抑制效应器T细胞渗入胃肠道来实现的。(3)确定类固醇反应的预测因子和 耐药患者的GI AGVHD。我们将检验这一假设：类固醇反应和类固醇反应的统一机制 通过对AGVHD的血液和胃肠道进行全面的关联免疫研究，可以确定患者的耐药性 诊断。通过完成这些目标，我们将弄清推动GI AGVHD的机制，从而从根本上 提高我们护理接受HCT患者的能力。

Novel Biologic Therapies for GVHD Abstract: For patients with high-risk malignant and non-malignant hematologic diseases, hematopoietic stem cell transplant (HCT) often represents the only option for cure. However, HCT is fraught with complications, leading to high rates of toxicity and patient death. The principal cause of early non-relapse mortality is acute graft-versus-host disease (AGVHD), with death from infection a close second. These two are interrelated, as intensifying global immune suppression to control AGVHD increases infection risk. Moreover, augmented immunosuppression can also increase the risk of malignant relapse. To move the field forward, we must develop targeted, evidence-based prevention and treatment strategies, designed to specifically control alloreactivity while preserving anti-tumor and anti-viral protective immunity. Perhaps the greatest need for these targeted therapeutics is in GI AGVHD, the leading cause of AGVHD- related death. Two issues predominate, which significantly impede progress: (1) We do not adequately understand the distinct mechanisms controlling GI T cell infiltration versus tissue residency or damage, which inhibits development of specific therapies. (2) We do not understand the mechanisms driving steroid-refractory GI AGVHD, significantly slowing treatment development for this most deadly type of AGVHD. The goal of this proposal is to address these unmet needs, and thereby discover the next generation of therapeutics for GI AGVHD. We will do so by completing the following three Specific Aims: (1): Prioritize and validate next-generation GI-targeted therapeutics with a novel translational pipeline. We will test the hypothesis that a pipeline from patient/NHP-derived therapeutic candidates → mouse → NHP AGVHD models can prioritize new AGVHD therapeutics. (2) Determine the impact of Notch ligand blockade on the blood and GI immune landscape in NHP and transplant patients. We will test the hypothesis that Notch ligand blockade with the anti-DLL4 mAb REGN421 protects against GI AGVHD, and that it does so by inhibiting effector T cell infiltration into the GI tract. (3) Identify predictors of steroid responsive and resistant GI AGVHD in patients. We will test the hypothesis that unifying mechanisms of steroid response and resistance can be identified in patients by comprehensive linked immune studies of the blood and GI tract at AGVHD diagnosis. By completing these aims, we will discern the mechanisms driving GI AGVHD, and thus fundamentally advance our ability to care for patients undergoing HCT.