Low Dose Interleukin-2 for Regulatory T cell Modulation and the Treatment of Crohn's Disease

项目摘要 炎症性肠病(IBD)是一种慢性疾病，由溃疡性结肠炎(UC)和克罗恩病(CD)组成 胃肠道疾病患病率迅速上升。尽管最近在治疗方面取得了进展，但一个显著的 患者对药物治疗的反应不佳的比例，留下了迫切需要寻找新的 治疗。一种有希望的治疗IBD的新方法是通过操纵调节性T细胞(Tregs)。 Tregs是一种免疫调节性的CD4+淋巴细胞亚群，可拮抗活化和效应功能 多种免疫细胞类型，促进对自身抗原的耐受性。经收养转移的树是有效的 在IBD的小鼠模型中。通过Treg操作进行疾病管理的另一种方法是 增加活体内的Treg数。白介素2(IL-2，Proil®)是一种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 人类Tregs的选择性激活和扩展。Tregs结构性表达CD25，CD25是Tregs的一个组成部分 高亲和力IL-2R，而CD25仅由激活的传统T效应细胞瞬时表达。低剂量 (LD)IL-2选择性地扩大人类的Tregs，对慢性GvHD和其他1、2期临床是安全的 审判。我们最近发表了LD IL-2对人源化IBD小鼠模型的保护作用。在此基础上 临床前数据，我们启动并几乎完成了LD IL-2在24名患者中的1b/2a期临床试验 加州大学。皮下(Sc)LD IL-2耐受性良好，与生物反应和pTreg扩张相关 UC：总体而言，41.6%的患者实现了缓解或缓解，其中包括60%的接受治疗的患者 最大有效剂量(MED)。有了这些令人兴奋的数据，我们已经开发了1b/2a期临床试验 评价LD SC IL-2治疗CD的安全性和有效性，并探讨其免疫调节作用 IL-2在外周免疫和粘膜免疫中的作用到目前为止，我们已经获得了：1)临时 IRB批准；2)FDA的研究新药(IND)批准；3)商业实体的支持 向患者免费提供药品。我们设计了一套全面的免疫表型策略来 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。在这项研究中，我们 建议：目的1：确定sc LD IL-2治疗中重度CD的安全性。我们建议 CD患者每日皮下注射IL-2 8周的1b/2a期临床试验 剂量(MED)和安全性概况，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，并与临床预后相关。我们 将对接受LD IL-2治疗的CD患者进行深入的免疫表型鉴定，并综合评估 LD IL-2对外周血和粘膜中的CD4+Tregs和其他免疫细胞的影响 免疫表型的变化与临床结果相关。总体而言，这项试验旨在确定 CD中LD IL-2的MED和安全性概况，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.