Low dose interleukin 2 for the expansion of regulatory T cells and the treatment of moderate to severe ulcerative colitis

项目摘要/摘要 由溃疡性结肠炎(UC)和克罗恩病(CD)组成的炎症性肠病(IBD)是 胃肠道慢性疾病，患病率迅速上升。尽管最近在治疗方面取得了进展，但 相当大比例的患者对药物治疗的反应不佳，迫切需要 确定新的治疗方法。一种很有希望的治疗IBD的新方法是通过操纵调节性T 细胞(树)。胸腺来源的Tregs是一种免疫调节的CD4淋巴细胞亚群，它能拮抗 多种免疫细胞类型的激活和效应功能，促进对自身抗原的耐受。 过继转移的Tregs在IBD小鼠模型中有效预防T细胞介导的和髓系的 细胞介导的结肠炎，而Treg细胞疗法在移植物抗宿主病(GvHD)的治疗中显示出希望 和1型糖尿病。一种通过Treg操作进行疾病管理的替代和有吸引力的方法 就是增加体内的Treg数量。 白介素2(IL-2，Proil®)是一种T细胞生长因子。IL-2目前被批准用于治疗 转移性肾细胞癌和转移性黑色素瘤。在低剂量时，IL-2促进选择性激活 以及Tregs在人类中的扩张。Tregs结构性地表达CD25，CD25是高亲和力IL-2R的一种成分， 而CD25只在激活的传统T效应细胞中瞬时表达。肿瘤学合作者 我们的团队最近证明，低剂量(LD)的IL-2在体内选择性地扩大人类体内的Tregs，并且是安全的 治疗慢性移植物抗宿主病，在1期和2期临床试验中有效。我们的初步数据显示LD IL-2 选择性地激活UC患者固有层(LP)细胞中的Tregs，并证明它对 人源化IBD小鼠模型。因此，我们假设LD IL-2将选择性地扩大Treg群体 在中到重度UC患者体内，这种扩张将与治疗相关 回应。 为了将这些临床前发现转化为患者的利益，我们启动了一项1b/2a期临床试验 结肠炎患者外周血中IL-2水平的变化到目前为止，我们已经招募了11名前两剂疫苗的患者。LD IL-2一直很好 耐受并已导致生物学反应，外周血Tregs在两个不同的 剂量。这项建议涉及两个具体目标：1)确定LD IL-2在治疗慢性粒细胞白血病中的安全性 中到重度UC，2)确定LD IL-2是否调节外周血和固有层 Tregs在UC的活体环境中的作用，并将其与临床结果相关联。这项试验的目的是确定 观察LD IL-2在本组患者中的最大耐受量和安全性，并获得疗效信号。

PROJECT SUMMARY/ABSTRACT 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). Thymically-derived 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 preventing both T cell-mediated and myeloid cell-mediated colitis, while Treg cell therapy has shown promise in the treatment of graft vs. host disease (GvHD) and type 1 diabetes. An alternative and attractive 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. Oncology collaborators on our team recently demonstrated that low-dose (LD) IL-2 selectively expands Tregs in humans in vivo and is safe in chronic GvHD, with efficacy in a phase 1 and 2 clinical trials. Our preliminary data shows that LD IL-2 selectively activates Tregs in lamina propria (LP) cells from patients with UC and that it is protective in a humanized mouse model of IBD. We therefore hypothesize that LD IL-2 will selectively expand Treg populations in vivo in patients with moderate-to-severe UC, and that expansion will be associated with a therapeutic response. To translate these pre-clinical findings to patient benefit, we have initiated a phase 1b/2a clinical trial of LD IL-2 in patients with UC. To date, we have enrolled 11 patients at the first two doses. LD IL-2 has been well tolerated and has resulted in a biological response, with an increase in peripheral blood Tregs at two different doses. This proposal addresses two specific aims: 1) To determine the safety of LD IL-2 in the treatment of moderate-to-severe UC, and 2) To determine whether LD IL-2 modulates peripheral blood and lamina propria Tregs in vivo in the setting of UC and to correlate this with clinical outcome. This trial is designed to determine the maximum tolerated dose and safety profile of LD IL-2 in this patient group, and to obtain a signal of efficacy.