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

低剂量 IL-2 用于调节 T 细胞和治疗克罗恩病

基本信息

批准号：
10447028
负责人：
Jessica R. Allegretti
金额：
$ 55.15万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10447028
关键词：
Adoptive Transfer Affinity Aldesleukin Autoantigens Autologous Biological Biological Products Blood Boston CD4 Positive T Lymphocytes CSF3 gene Cells Charge Chronic Chronic Disease Clinical Clinical Research Clinical Trials Crohn&apos s disease Cytometry Cytotoxic T-Lymphocytes Data Digestive System Disorders Disease Disease Management Disease remission Dose FOXP3 gene Failure Food and Drug Administration Drug Approval Goals Granulocyte-Macrophage Colony-Stimulating Factor Hepatitis C Therapy Homeostasis Hospitals Human IL17 gene IL2 gene IL2RA gene Immune Immune response Immunomodulators Immunophenotyping Inflammatory Bowel Diseases Institutional Review Boards Insulin-Dependent Diabetes Mellitus Integrins Interleukin 2 Receptor Interleukin-2 Investigational Drugs Janus kinase Lactobacillus Lamina Propria Mediating Medical Metastatic Melanoma Metastatic Renal Cell Cancer Molecular Analysis Monoclonal Antibody HuM291 Mucous Membrane Mus Mutation Natural Killer Cells Oncology Oral Outcome Patients Pediatric Crohn&apos s disease Pediatric Hospitals Pediatric ulcerative colitis Peripheral Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Phenotype Population Positioning Attribute Predictive Factor Predisposition Prevalence Proteins Publishing Refractory Regulatory T-Lymphocyte Safety Signal Transduction Subgroup Systemic Lupus Erythematosus TNF gene Tacrolimus Testing Time Treg therapy Ulcerative Colitis Vasculitis Woman analysis pipeline anti-cancer base cancer therapy cell type chronic graft versus host disease clinical predictors design effector T cell experience graft vs host disease gut inflammation high dimensionality humanized mouse immunoregulation in vivo kinase inhibitor man medical schools mouse model murine colitis novel strategies novel therapeutics peripheral blood pre-clinical prevent research facility response subcutaneous transcriptomics translational medicine treatment response

项目摘要

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.

项目概要炎症性肠病 (IBD)，包括溃疡性结肠炎 (UC) 和克罗恩病 (CD)，是一种慢性疾病尽管最近在治疗方面取得了进展，但胃肠道疾病的患病率仍呈显着上升趋势。部分患者对药物治疗的反应不佳，迫切需要确定新的治疗方法治疗 IBD 的一种有前途的新方法是通过调节调节性 T 细胞 (Treg)。 Tregs 是 CD4+ 淋巴细胞的免疫调节子集，可拮抗激活和效应功能多种免疫细胞类型并促进对自身抗原的耐受性，过继转移的 Tregs 是有效的。在 IBD 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体内 Treg 数量 IL-2（IL-2，Proleukin®）是目前获得许可的 T 细胞生长因子。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 可促进转移性肾细胞癌和转移性黑色素瘤的治疗。人类中 Tregs 的选择性激活和扩增持续表达 CD25（CD25 的一个组成部分）。高亲和力 IL-2R，而 CD25 仅由激活的低剂量常规 T 效应细胞瞬时表达。 (LD) IL-2 选择性地扩增人类中的 Tregs，并且在慢性 GvHD 和其他 1 期和 2 期临床中是安全的基于此，我们最近发表了 LD IL-2 对 IBD 人源化小鼠模型具有保护作用的研究。根据临床前数据，我们启动并几乎完成了 LD IL-2 在 24 名患有以下疾病的患者中进行的 1b/2a 期临床试验： UC。皮下 (sc) LD IL-2 具有良好的耐受性并与生物反应和 pTreg 扩增相关。 UC：总体而言，41.6% 的患者达到缓解或缓解，其中包括 60% 的接受治疗的患者有了最大有效剂量（MED），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，并研究免疫调节作用 IL2 在外周和粘膜免疫区室中的影响迄今为止，我们已经获得： 1) 临时的。 IRB 批准；2) FDA 的研究性新药 (IND) 批准；3) 商业实体的支持；我们设计了一个全面的免疫表型分析策略来免费向患者提供药物。在这项研究中，我们评估了 LD IL-2 的生物学效应，并将这些发现与临床结果相关联。建议：目标 1：确定 sc LD IL-2 治疗中重度 CD 的安全性。在 CD 患者中进行每日皮下 LD IL-2 为期 8 周的 1b/2a 期临床试验，以确定最大有效性剂量（MED）和安全性概况，并评估疗效信号目标 2：确定 CD 患者是否。 sc LD IL-2 在体内调节外周血和固有层 Tregs 并与临床结果相关。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 对外周和粘膜区室中 CD4+ Tregs 和其他免疫细胞的影响，以及总体而言，该试验旨在确定免疫表型的变化与临床结果。 LD IL-2 在 CD 中的 MED 和安全性概况，以获得疗效信号并评估机制基础。