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

项目总结/摘要 炎症性肠病（IBD），包括溃疡性结肠炎（UC）和克罗恩病（CD）， 慢性胃肠道疾病，患病率迅速增加。尽管最近在治疗方面取得了进展， 很大一部分患者对药物治疗的反应不佳，因此迫切需要 找出新的疗法。一种有希望的治疗IBD的新方法是通过操纵调节性T细胞， 细胞（Tcells）。胸腺源性T淋巴细胞是CD4+淋巴细胞的免疫调节亚群，其拮抗 多种免疫细胞类型的激活和效应子功能，并促进对自身抗原的耐受性。 连续转移的THBE在IBD的鼠模型中有效地预防T细胞介导的和髓样的炎症。 细胞介导的结肠炎，而Treg细胞疗法在治疗移植物抗宿主病（GvHD）方面显示出前景 和1型糖尿病。通过Treg操纵进行疾病管理的替代和有吸引力的方法 就是增加体内Treg的数量 白细胞介素-2（IL-2，Proleukin®）是T细胞生长因子。IL-2目前被许可用于治疗 转移性肾细胞癌和转移性黑素瘤。在低剂量下，IL-2促进选择性激活 和人类中的TdR的扩张。T细胞组成型表达CD25，高亲和力IL-2R的组分， 而CD25仅由活化的常规T效应细胞瞬时表达。肿瘤学合作者 我们的研究小组最近证明，低剂量（LD）IL-2在体内选择性地扩增人类TcR，并且是安全的。 在慢性GvHD中，在1期和2期临床试验中具有疗效。我们的初步数据显示LD IL-2 选择性激活UC患者的固有层（LP）细胞中的TGFAP， IBD的人源化小鼠模型。因此，我们假设LD IL-2将选择性地扩增Treg群体， 在中重度UC患者体内进行，并且这种扩展将与治疗相关 反应 为了将这些临床前发现转化为患者获益，我们启动了一项1b/2a期临床试验， UC患者中的LD IL-2。到目前为止，我们已经招募了11名患者接受前两次剂量。白介素-2已经很好地 耐受，并导致生物反应，在两个不同的外周血T细胞增加， 剂量该建议涉及两个具体目标：1）确定LD IL-2治疗以下疾病的安全性： 中度至重度UC，和2）确定LD IL-2是否调节外周血和固有层 在UC的背景下进行体内试验，并将其与临床结果相关联。这个试验是为了确定 LD IL-2在该患者组中的最大耐受剂量和安全性特征，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.