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

摘要 原发性免疫调节性疾病(PIRD)是一组先天性免疫缺陷(IEI)，由以下原因引起 特定免疫途径的结构性激活和/或失调。到目前为止，已鉴定出130个基因。 与PIRD相关的基因。每个PIRD都是极其罕见的，PIRD一般包括大约 5%的IEI。患有PIRDS的患者通常有多种危及生命的机会性感染、自体炎症 病情和自身免疫后遗症与其免疫系统的持续激活有关。鉴于这种稀有的 在每个PIRD和PIRD的总体上，对这些患者的治疗干预即使有，也很少。 造血干细胞移植(HCT)为许多PIRDS患者提供了一个治疗选择。高水平 然而，炎性介质在PIRDS患者中的应用使其非常难以成功 结果主要是由于移植失败/排斥以及移植后的免疫并发症。患有疾病的患者 因此，PIRD的治疗选择有限，只有受影响最严重的才会被考虑 用于治疗红细胞压积。Bridge试验是一项第二阶段的临床试验，旨在通过 诊断为PIRD的患者的红细胞压积。该方案利用了生物标记物引导的免疫抑制前期 以减少炎症环境之前和期间的清髓性调节方案的红细胞压积。对病人来说 PIRD导致其干扰素γ途径的扰动，emapalab的前期，干扰素γ的中和 在调理方案之前和期间将加入单抗。患有PIRD的患者 导致其他炎症途径失调的疾病将受到全身性炎症抑制 氟达拉滨和地塞米松的前期应用，类似于目前用于 接受红细胞压积治疗的血红蛋白疾病。这些有针对性的炎症抑制方案将提供更多 PIRD患者在接受条件化处理并实现更有效植入时的平衡环境， 平衡的免疫重建和改善的结果。此数据集将是扩展以下各项适应症的关键 Emaplaumab是一种孤儿药物，被批准用于原发性噬血细胞淋巴组织细胞增多症(PHLH)，以桥接 干扰素γ免疫紊乱综合征根治性血细胞移植的治疗在目标2和目标3中，我们利用我们的 在免疫重建和生物标志物发现研究方面的专业知识，以提供深入的相关生物学研究。我们的 重点将集中在重组亚群的深层免疫表型，识别可溶的生物标记物 免疫介导的并发症和识别早期靶向免疫抑制的机制 有助于在调节期间和在造血系统再生时提供适当的免疫环境 在HCT之后。这些研究将为未来继续进行临床试验提供关键数据，以提供持久的治疗方法 被诊断为PIRD的患者。

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.