Low Dose Interleukin-2 for Regulatory T cell Modulation and the Treatment of Crohnâs Disease

项目摘要 炎症性肠病（IBD）包括溃疡性结肠炎（UC）和克罗恩病（CD），是慢性炎症性肠病， 胃肠道疾病的发病率迅速上升。尽管最近在治疗方面取得了进展， 部分患者对药物治疗的反应不佳，因此迫切需要确定新的 治疗治疗IBD的一种有前途的新方法是通过操纵调节性T细胞（Tcells）。 T细胞是CD 4+淋巴细胞的免疫调节亚群，其拮抗活化和效应子功能， 多种免疫细胞类型，并促进对自身抗原的耐受性。已转让的TMF有效 在IBD的小鼠模型中。通过Treg操纵进行疾病管理的替代方法是 增加体内Treg数量。白细胞介素-2（IL-2，Proleukin®）是T细胞生长因子。IL-2目前已获得许可 用于治疗转移性肾细胞癌和转移性黑色素瘤。在低剂量时，IL-2促进 在人类中选择性激活和扩增T细胞。T细胞组成性表达CD 25，CD 25是T细胞的一个组成部分。 高亲和力IL-2 R，而CD 25仅由活化的常规T效应细胞瞬时表达。低剂量 (LD)IL-2选择性地扩增人类中的TcR，并且在慢性GvHD和其他1期和2期临床试验中是安全的。 审判我们最近发表了LD IL-2在IBD的人源化小鼠模型中具有保护作用。基于此 临床前数据，我们启动并几乎完成了LD IL-2在24例患者中的1b/2a期临床试验， 加州大学皮下（sc）LD IL-2耐受性良好，并与生物学反应和pTreg扩增相关 UC：总体而言，41.6%的患者达到缓解或缓解，包括60%的治疗患者 最大有效剂量（MED）有了这些令人兴奋的数据，我们开发了一项1b/2a期临床试验， 评估LD SC IL-2治疗CD的安全性和有效性，并研究其免疫调节作用。 IL 2在外周和粘膜免疫区室中的作用。迄今为止，我们已获得：1）临时 IRB批准; 2）FDA的研究性新药（IND）批准; 3）商业实体的支持 为病人免费提供药品。我们设计了一个全面的免疫分型策略， 评估LD IL-2的生物学效应，并将这些发现与临床结果相关联。本研究 目的：1：确定皮下LD IL-2治疗中重度CD的安全性。我们提出 一项在CD患者中进行的1b/2a期临床试验，每日皮下注射LD IL-2，持续8周，以确定最大有效 剂量（MED）和安全性特征，并评估疗效信号。目的2：确定CD患者是否 sc LD IL-2在体内调节外周血和固有层T细胞，并与临床结果相关。我们 将在接受LD IL-2治疗的CD患者中进行深度免疫表型分析，并全面评估 LD IL-2对外周和粘膜隔室中的CD 4 + T细胞和其他免疫细胞的作用，以及 将免疫表型变化与临床结果相关联。总体而言，本试验旨在确定 LD IL-2在CD中的MED和安全性特征，以获得疗效信号，并评估机制基础。

Project Summary Inflammatory bowel disease (IBD), comprised of ulcerative colitis (UC) and Crohn's disease (CD) are chronic disorders of the GI tract with rapidly increasing prevalence. Despite recent advances in treatment, a significant proportion of patients have suboptimal responses to medical therapy, leaving an urgent need to identify new therapies. One promising new approach to treat IBD is through the manipulation of regulatory T cells (Tregs). Tregs are an immune modulating subset of CD4+ lymphocytes that antagonize the activation and effector function of multiple immune cell types and promote tolerance to self-antigens. Adoptively transferred Tregs are effective in murine models of IBD. An alternative approach to disease management through Treg manipulation is to increase Treg numbers in vivo. Interleukin-2 (IL-2, Proleukin®) is a T cell growth factor. IL-2 is currently licensed for the treatment of metastatic renal cell carcinoma and metastatic melanoma. At low doses, IL-2 promotes the selective activation and expansion of Tregs in humans. Tregs constitutively express CD25, a component of the high-affinity IL-2R, while CD25 is only transiently expressed by activated conventional T effector cells. Low-dose (LD) IL-2 selectively expands Tregs in humans and is safe in chronic GvHD and other phase 1 and 2 clinical trials. We recently published that LD IL-2 is protective in a humanized mouse model of IBD. Based on this preclinical data, we initiated and have almost completed a Phase 1b/2a clinical trial of LD IL-2 in 24 patients with UC. Subcutaneous (sc) LD IL-2 is well tolerated and associated with a biological response and pTreg expansion in UC: overall, 41.6% of patients have achieved either response or remission including 60% of patients treated with the maximum effective dose (MED). With this exciting data, we have developed a Phase 1b/2a clinical trial to assess the safety and the efficacy of LD SC IL-2 for the treatment of CD and to study the immunoregulatory effects of IL2 in the peripheral and mucosal immune compartments. To date, we have obtained: 1) provisional IRB approval; 2) an Investigational New Drug (IND) approval from the FDA; 3) support from commercial entities to supply drug free of charge to patients. We have designed a comprehensive immunophenotyping strategy to assess the biological effects of LD IL-2 and to correlate these findings with clinical outcomes. In this study we propose: Aim 1: To determine the safety of sc LD IL-2 in the treatment of moderate-to-severe CD. We propose a phase 1b/2a clinical trial of daily sc LD IL-2 for 8 weeks in CD patients to determine the maximum effective dose (MED) and safety profile, and to assess a signal of efficacy. Aim 2: To determine in CD patients whether sc LD IL-2 modulates peripheral blood and lamina propria Tregs in vivo and correlates with clinical outcome. We will perform deep immunophenotyping in CD patients treated with LD IL-2 and comprehensively assess the effects of LD IL-2 on CD4+ Tregs and other immune cells in both peripheral and mucosal compartments, and correlate changes in immune phenotype with clinical outcome. Overall this trial is designed to determine the MED and safety profile of LD IL-2 in CD, to obtain a signal of efficacy, and to assess mechanistic underpinnings.