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

低剂量白介素 2 用于扩增调节性 T 细胞并治疗中度至重度溃疡性结肠炎

基本信息

批准号：
9767767
负责人：
Jessica R. Allegretti
金额：
$ 17.24万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-21 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767767
关键词：
Address Adoptive Transfer Affinity Agreement Aldesleukin Applications Grants Autoantigens Basic Science Biological Biological Products Boston CD19 gene CD4 Positive T Lymphocytes CSF3 gene Cell Therapy Cells Charge Childhood Chronic Chronic Disease Clinical Clinical Research Clinical Trials Colitis Crohn&apos s disease Cytotoxic T-Lymphocytes Dana-Farber Cancer Institute Data Digestive System Disorders Dipeptidyl-Peptidase IV Disease Management Disease remission Dose Enrollment FOXP3 gene Food and Drug Administration Drug Approval Funding Granulocyte-Macrophage Colony-Stimulating Factor Hepatitis C Therapy Homeostasis Hospitals Human IL2RA gene Immune Immune response Immunomodulators Immunophenotyping Inflammation Inflammatory Bowel Diseases Inflammatory disease of the intestine Institutional Review Boards Insulin-Dependent Diabetes Mellitus Integrins Interleukin 2 Receptor Interleukin-2 Intestines Investigational Drugs Laboratories Lactobacillus Lamina Propria Lupus Maintenance Maximum Tolerated Dose Mediating Medical Metastatic Melanoma Metastatic Renal Cell Cancer Modeling Molecular Abnormality Monoclonal Antibody HuM291 Mucous Membrane Muromonab-CD3 Mus Mutation Myeloid Cells Natural Killer Cells Oral Organ Outcome Patients Pediatric Hospitals Peripheral Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Phenotype Population Predisposition Prevalence Regulatory T-Lymphocyte Safety Signal Transduction Solid T-Lymphocyte TNF gene TNFRSF8 gene Tacrolimus Thymus Gland Time Translating Ulcerative Colitis Woman anti-cancer cancer therapy cell type chronic graft versus host disease design effector T cell experience graft vs host disease humanized mouse immune activation in vivo man mouse model novel strategies novel therapeutics oncology peripheral blood pre-clinical prevent research facility response subcutaneous translational medicine treatment response

项目摘要

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.

项目概要/摘要炎症性肠病 (IBD)，包括溃疡性结肠炎 (UC) 和克罗恩病 (CD) 尽管最近在治疗方面取得了进展，但慢性胃肠道疾病的患病率仍在迅速增加。很大一部分患者对药物治疗的反应不佳，迫切需要治疗 IBD 的一种有前景的新方法是通过调节调节 T 来确定新疗法。胸腺来源的 Tregs 是具有拮抗作用的 CD4+ 淋巴细胞的免疫调节子集。多种免疫细胞类型的激活和效应功能，并促进对自身抗原的耐受性。过继转移的 Tregs 在 IBD 小鼠模型中有效预防 T 细胞介导的和骨髓性的 IBD 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，这是一种通过 Treg 调控进行疾病管理的替代且有吸引力的方法。就是增加体内Treg数量。 Interleukin-2（IL-2，Proleukin®）是一种 T 细胞生长因子，目前已获许可用于治疗以下疾病。低剂量时，IL-2 可促进转移性肾细胞癌和转移性黑色素瘤的选择性激活。人类中 Tregs 的扩增持续表达 CD25（高亲和力 IL-2R 的一个组成部分）而 CD25 仅由激活的常规 T 效应细胞短暂表达。我们的团队最近证明，低剂量 (LD) IL-2 可选择性地扩增人体体内的 Tregs，并且是安全的在慢性 GvHD 中，1 期和 2 期临床试验显示 LD IL-2 有效。选择性激活 UC 患者固有层 (LP) 细胞中的 Tregs，并且它在因此，我们认为 LD IL-2 会选择性地扩大 Treg 群体。在中度至重度 UC 患者体内，这种扩展将与治疗相关回复。为了将这些临床前研究结果转化为患者利益，我们启动了 1b/2a 期临床试验 LD IL-2 在 UC 患者中的应用迄今为止，我们已经招募了 11 名患者，前两剂 LD IL-2 效果良好。耐受并导致生物反应，在两种不同的情况下外周血 Tregs 增加该提案涉及两个具体目标：1) 确定 LD IL-2 在治疗中的安全性。中度至重度 UC，以及 2) 确定 LD IL-2 是否调节外周血和固有层 UC 设置中的体内 Tregs 并将其与临床结果关联起来。本试验旨在确定。 LD IL-2 在该患者组中的最大耐受剂量和安全性概况，并获得疗效信号。