Phase 1 Study of Autologous CD4LVFOXP3 in Participants with IPEX Syndrome [revised IND and clinical protocol to be submitted to FDA by 10/11/2021]

IPEX 综合征参与者自体 CD4LVFOXP3 的 1 期研究 [修订后的 IND 和临床方案将于 2021 年 10 月 11 日提交给 FDA]

• 批准号: 10503570
• 负责人: Rosa Bacchetta
• 金额: $ 66.85万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503570
• 关键词: Phase; Study; Autologous; CD4LVFOXP3; Participants

Project Summary We propose a novel regulatory T (Treg) cell therapy to treat IPEX syndrome, a rare autoimmune monogenic disease. IPEX is a life-threatening disease caused by loss-of-function FOXP3 mutations leading to dysfunctional Treg cells. The only current curative treatment for IPEX is allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is only available to a minority of patients. The proposed product, CD4LVFOXP3 consists of autologous CD4+ T cells that have undergone lentiviral vector (LV)-mediated gene transfer of wild-type human FOXP3 leading to persistent high FOXP3 expression and acquisition of Treg cell phenotype and function. CD4LVFOXP3 were granted Orphan Drug designation in October, 2020. Based on the etiology of IPEX, our hypothesis is that the administration of autologous CD4+ T cells converted into CD4LVFOXP3 Treg-like cells by LV-mediated FOXP3 gene transfer, will reduce the immune dysregulation and the autoimmune manifestations. CD4LVFOXP3 is functionally equivalent to Treg cells and therefore, offer a novel cell therapy approach that circumvents the requirement for generalized immune suppression (IS) and could improve the clinical status of participants. This First-Time-in-Human (FTiH) Phase 1 clinical trial will test the feasibility of the manufacturing and the safety of the administration of CD4LVFOXP3 (Aim 1) in minimum of 20 up to 36 evaluable human participants with IPEX, who meet eligibility criteria. The secondary objective is to evaluate the impact of the CD4LVFOXP3 infusion on clinical manifestations. The dosing rationale has been developed with a conservative approach based on initial cell doses used in previous clinical trials with Treg cells of different origins. CD4LVFOXP3 also express membrane NGFR (CD271) encoded within the same LV construct that contains the FOXP3 gene. allowing ex vivo purification and traceability enabling further studies of CD4LVFOXP3survival, phenotypic stability and functional characteristics. Thus, during this clinical trial, we will perform exploratory studies to build knowledge on the CD4LVFOXP3 pharmacokinetics (PK) (Aim2) and pharmacodynamics (PD) (Aim 3) by monitoring the immune phenotype and function of patient immune cells. The possibility to provide functional autologous Treg-like cells is expected to be of benefit to all eligible IPEX patients. CD4LVFOXP3 could: 1. improve control of clinical manifestations resulting in the reduction of IS and related side effects, and 2. diminish the need for allo- HSCT, or allow patients to be transplanted in a more stable clinical condition, resulting in improved allo-HSCT outcomes. Successful completion of this clinical trial in patients with IPEX using CD4LVFOXP3 Treg-like cells as a functional replacement for FOXP3 mutated Treg cells, addresses a significant unmet medical need while also providing proof of safety and preliminary indications of benefit in controlling autoimmune disease manifestations. As such, data from this trial could lead to expanded application of autologous CD4LVFOXP3 to other Tregopathies and/or other more common autoimmune disorders, such as inflammatory bowel disease (IBD), type 1 diabetes (T1D), cytopenia and atopic dermatitis, all of which have overlapping disease manifestations in IPEX patients.

项目概要 我们提出了一种新型调节性 T (Treg) 细胞疗法来治疗 IPEX 综合征，这是一种罕见的自身免疫性单基因疾病 疾病。 IPEX 是一种危及生命的疾病，由 FOXP3 功能丧失突变导致功能障碍 Treg 细胞。目前IPEX唯一的治疗方法是同种异体造血干细胞移植 （allo-HSCT），仅适用于少数患者。提议的产品 CD4LVFOXP3 包括 经过慢病毒载体 (LV) 介导的野生型人类基因转移的自体 CD4+ T 细胞 FOXP3 导致 FOXP3 持续高表达并获得 Treg 细胞表型和功能。 CD4LVFOXP3于2020年10月被授予孤儿药资格。根据IPEX的病因学，我们的 假设是自体 CD4+ T 细胞的施用转化为 CD4LVFOXP3 Treg 样细胞 通过LV介导的FOXP3基因转移，将减少免疫失调和自身免疫 表现形式。 CD4LVFOXP3 在功能上与 Treg 细胞等效，因此提供了一种新型细胞疗法 该方法规避了广义免疫抑制（IS）的要求，并且可以改善 参与者的临床状况。这项首次人体 (FTiH) 1 期临床试验将测试该技术的可行性 CD4LVFOXP3 的制造和管理安全性（目标 1）至少 20 至 36 个可评估的 符合资格标准的 IPEX 人类参与者。第二个目标是评估影响 CD4LVFOXP3输注对临床表现的影响。剂量原理是按照保守的原则制定的 该方法基于先前不同来源的 Treg 细胞临床试验中使用的初始细胞剂量。 CD4LVFOXP3 还表达在包含 FOXP3 基因的同一 LV 构建体中编码的膜 NGFR (CD271)。 允许离体纯化和可追溯性，从而能够进一步研究 CD4LVFOXP3 存活、表型稳定性 和功能特点。因此，在本次临床试验期间，我们将进行探索性研究来建立 通过监测了解 CD4LVFOXP3 药代动力学 (PK) (目标 2) 和药效学 (PD) (目标 3) 患者免疫细胞的免疫表型和功能。提供功能性自体同体的可能性 Treg 样细胞预计将使所有符合条件的 IPEX 患者受益。 CD4LVFOXP3 可以： 1. 提高控制能力 临床表现导致 IS 和相关副作用的减少，以及 2. 减少同种异体的需要 HSCT，或让患者在临床状况更稳定的情况下进行移植，从而获得改良的allo-HSCT 结果。使用 CD4LVFOXP3 Treg 样细胞作为 IPEX 患者的临床试验成功完成 FOXP3 突变 Treg 细胞的功能替代品，解决了未满足的重大医疗需求，同时还 提供安全性证据和控制自身免疫性疾病表现的益处的初步迹象。 因此，该试验的数据可能会导致自体 CD4LVFOXP3 扩大应用于其他 Tregopathies 和/或其他更常见的自身免疫性疾病，例如炎症性肠病 (IBD)、1 型糖尿病 (T1D)、血细胞减少和特应性皮炎，所有这些在 IPEX 患者中都有重叠的疾病表现。