Phase 2 Bridging Pre-transplant Inflammatory Dampening for Primary Immune Regulatory Disorders (BRIDGE Trial)

第二阶段桥接移植前炎症抑制治疗原发性免疫调节紊乱（BRIDGE 试验）

• 批准号: 10861608
• 负责人: Joseph H Oved
• 金额: $ 64.81万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10861608
• 关键词: Phase; Bridging; Pre; transplant; Inflammatory

Abstract The Primary Immune Regulatory Disorders (PIRDs) are a group of inborn errors of immunity (IEI) that result from constitutive activation and/or dysregulation of specific immune pathways. There are 130 genes identified to date that are associated with PIRDs. Each PIRD is extremely rare and the PIRDs in general comprise approximately 5% of IEI. Patients with PIRDs often have multiple life-threatening opportunistic infections, autoinflammatory conditions and autoimmune sequelae related to the constant activation of their immune system. Given the rarity of each PIRD and of PIRDs in general there are little if any therapeutic interventions for these patients. Hematopoietic Stem Cell Transplant (HCT) offers a curative option for many patients with PIRDs. The high levels of inflammatory mediators in patients with PIRDs however has made it extremely difficult to have successful outcomes due mostly to graft failure/rejection as well as post-transplant immune complications. Patients with PIRDs therefore have limited therapeutic options and only those that are most severely affected are considered for cures with HCT. The BRIDGE Trial is a Phase 2 clinical trial to improve outcomes of curative therapy with HCT for patients with a PIRD diagnosis. The protocol utilized a biomarker-guided immune suppression prophase to dampen the inflammatory milieu prior to and during a myeloablative conditioning regimen for HCT. For patients with PIRDs that result in perturbations of their IFNγ pathway, a prophase of emapalumab, an IFNγ neutralizing monoclonal antibody will be incorporated prior to and during the conditioning regimen. Patients that have PIRDs that result in dysregulation of other inflammatory pathways will receive a generalized inflammatory suppression prophase with fludarabine and dexamethasone, similar to what is currently being used for patients with hemoglobinopathies undergoing HCT. These targeted inflammatory suppression regimens will provide a more balanced milieu in patients with PIRDs while they receive conditioning and enable more efficient engraftment, balanced immune reconstitution and improved outcomes. This dataset will be pivotal to expand indications for emaplaumab, an orphan drug approved for primary hemophagocytic lymphohistiocytosis (pHLH), to bridging therapy for curative HCT for IFNγ immune dysregulation syndromes. In aims 2 and 3 we take advantage of our expertise in immune reconstitution and biomarker discovery studies to provide in-depth correlative biology. Our focus will center on deep immunophenotyping of reconstituting subsets, identification of soluble biomarkers for immune mediated complications and to identify mechanisms of how a targeted immune suppression prophase helps provide an appropriate immune milieu during conditioning and as the hematopoietic system regenerates after HCT. These studies will provide critical data for continued future clinical trials to provide durable cures to patients with PIRD diagnoses.

抽象的 原发性免疫调节障碍 (PIRD) 是一组先天性免疫缺陷 (IEI)，其原因是 特定免疫途径的组成性激活和/或失调。迄今为止已鉴定出130个基因 与 PIRD 相关的。每个 PIRD 都极其罕见，并且 PIRD 通常包含大约 IEI 的 5%。 PIRD 患者通常患有多种危及生命的机会性感染、自身炎症 与免疫系统持续激活有关的病症和自身免疫后遗症。鉴于其稀有性 对于每个 PIRD 以及一般的 PIRD，针对这些患者的治疗干预措施几乎没有（如果有的话）。 造血干细胞移植 (HCT) 为许多 PIRD 患者提供了一种治疗选择。高水平 然而，PIRD 患者体内炎症介质的含量过高使得成功治疗变得极其困难。 结果主要是由于移植失败/排斥以及移植后免疫并发症。患者患有 因此，PIRD 的治疗选择有限，仅考虑那些受影响最严重的患者 用于 HCT 治疗。 BRIDGE 试验是一项 2 期临床试验，旨在改善治疗效果 针对 PIRD 诊断患者的 HCT。该方案利用生物标志物引导的免疫抑制前期 在 HCT 清髓性预处理方案之前和期间抑制炎症环境。对于患者 PIRD 会导致其 IFNγ 通路扰动，emapalumab 是一种 IFNγ 中和剂的前期 单克隆抗体将在预处理方案之前和期间掺入。患有 PIRD 的患者 导致其他炎症途径失调的炎症将受到普遍的抑制 前期使用氟达拉滨和地塞米松，类似于目前用于患有以下疾病的患者 接受 HCT 的血红蛋白病。这些有针对性的炎症抑制方案将提供更多 PIRD 患者在接受调理时保持平衡的环境，并实现更有效的植入， 平衡的免疫重建和改善的结果。该数据集对于扩大适应症至关重要 emaplaumab 是一种孤儿药，被批准用于治疗原发性噬血细胞性淋巴组织细胞增多症 (pHLH)，以桥接 治疗 IFNγ 免疫失调综合征的 HCT 疗法。在目标 2 和 3 中，我们利用我们的优势 免疫重建和生物标志物发现研究方面的专业知识，可提供深入的相关生物学。我们的 重点将集中于重建子集的深度免疫表型分析、可溶性生物标志物的鉴定 免疫介导的并发症并确定靶向免疫抑制前期的机制 有助于在调理期间和造血系统再生时提供适当的免疫环境 HCT 后。这些研究将为未来持续的临床试验提供关键数据，以提供持久的治疗方法 患有 PIRD 诊断的患者。