Defining the T Cell Mediators of Clinical Response in Chronic GVHD

定义慢性 GVHD 临床反应的 T 细胞介质

基本信息

批准号：
10698167
负责人：
Leslie S Kean
金额：
$ 46.63万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10698167
关键词：
AREG gene Adoptive Cell Transfers Automobile Driving Biological Markers Blood CD28 gene CD80 gene Candidate Disease Gene Cell Therapy Cells Cellular biology Chronic Classification Clinical Clinical Data Collaborations Data Development Disease Dose Engineering Epitopes Evolution Failure Flow Cytometry Functional disorder Gene Modified Generations Genes Goals Hematopoietic Stem Cell Transplantation Human Immune Immunologics In complete remission Interleukin-2 Libraries Link Lung Mediator Modality Molecular Morbidity - disease rate Mus Outcome Pathogenesis Pathway interactions Patients Phosphotransferases Population Positioning Attribute Prevention strategy Prophylactic treatment ROCK1 gene Refractory Regulatory T-Lymphocyte Resistance Risk Sampling Signal Transduction Steroids T-Lymphocyte Testing Therapeutic Time Tissues Training Transplant Recipients Treatment Protocols Validation Work adjudication biobank chemokine chronic graft versus host disease clinical development cytokine design diagnostic signature dimensional analysis disease diagnosis experience individual patient inhibitor insight interleukin-21 mortality mouse model next generation novel therapeutics partial response profiles in patients quality assurance repository responders and non-responders response rho success transcriptome sequencing transcriptomics treatment response treatment strategy

项目摘要

Project 1: Defining the T Cell Mediators of Clinical Response in Chronic GVHD Abstract: Chronic graft versus host disease (cGVHD) represents the major cause of morbidity and late mortality after hematopoietic stem cell transplantation (HCT). While multiple innate and adaptive immune cell populations contribute to its’ pathophysiology, donor T cells orchestrate cGVHD at all stages, either through their direct effects, or through their influence on other cell populations. However, despite detailed information about the mechanisms controlling cGVHD derived from mouse models, and the development of several new clinical therapeutics, the rates of complete response (CR) remain low: most patients demonstrate only a partial response to therapy, and many have therapy-refractory cGVHD. Moreover, there is a critical lack of information about what determines clinical response in individual patients treated for cGVHD. To make breakthroughs in our understanding of the pathogenesis of human cGVHD and to prioritize the next generation of therapeutics, we must (1) Accurately define the immune pathways that are active in patients who ultimately develop cGVHD and (2) Determine the mechanisms of both success and failure of cGVHD treatment regimens at the level of the individual patient. To accomplish these goals, this Project will complete the following Specific Aims. In Aim 1, we will identify Risk Assignment immune profiles for cGVHD at Day +100. In Aim 2, we will determine the evolution of treatment-responsive versus -resistant immune profiles in patients with cGVHD. In Aim 3 we will investigate the impact of gene modification of Tregs based on completed trajectory analyses from responders versus non-responders to low-dose IL-2, in order to create an optimized cellular therapeutic to control cGVHD. By accomplishing these Aims, this Project promises to identify the molecular networks that predict cGVHD, and those associated with response or resistance to cGVHD therapies, thereby paving the way for a new era of successful prevention and treatment strategies for this disease.

项目1：定义慢性GVHD中临床反应的T细胞介质抽象的：慢性移植与宿主疾病（CGVHD）代表了发病率和死亡率晚期的主要原因造血干细胞移植（HCT）。而多个先天和适应性免疫池种群供体T细胞在各个阶段进行供体T细胞来促进CGVHD，要么通过其直接影响，或通过其对其他细胞群体的影响。但是，dospite有关控制源自小鼠模型的CGVHD的机制，以及几个新临床的发展治疗，完全反应率（CR）仍然很低：大多数患者仅表现出部分对治疗的反应，许多人患有治疗 - 不良CGVHD。而且，严重缺乏有关确定接受CGVHD治疗的个别患者临床反应的信息。做在我们对人CGVHD发病机理的理解中的突破并优先考虑下一代从理论上讲，我们必须（1）准确定义最终患者活跃的免疫途径开发CGVHD，（2）确定CGVHD处理方案成功和失败的机制在个别患者的水平上。为了实现这些目标，该项目将完成以下特定目标。在AIM 1中，我们将在第+100天确定CGVHD的风险分配免疫配置。在AIM 2中，我们将确定CGVHD患者的治疗反应性与抗性免疫谱的演变。在 AIM 3我们将根据完整的轨迹分析研究Treg的基因修饰的影响响应者与低剂量IL-2的反应者相对于非反应者，以创建优化的细胞疗法来控制 CGVHD。通过完成这些目标，该项目有望确定预测的分子网络 CGVHD以及与CGVHD疗法的反应或抵抗相关的cGVHD，从而为成功预防和治疗策略的新时代。