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：
10493799
负责人：
Leslie S Kean
金额：
$ 47.88万
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/10493799
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 Clinical Clinical Data 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 Investigation Libraries Link Lung Mediator of activation protein 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 base biobank chemokine chronic graft versus host disease clinical development cytokine design diagnostic signature disease diagnosis experience immune resistance individual patient insight model development 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 trial comparing

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 临床反应的 T 细胞介质抽象的：慢性移植物抗宿主病（cGVHD）是术后发病和晚期死亡的主要原因。造血干细胞移植（HCT），同时多种先天性和适应性免疫细胞群。供体 T 细胞在各个阶段协调 cGVHD，无论是通过其直接影响，或通过它们对其他细胞群的影响然而，尽管有详细的信息。源自小鼠模型的控制 cGVHD 的机制，以及几种新的临床药物的开发治疗方面，完全缓解 (CR) 率仍然很低：大多数患者仅表现出部分缓解治疗反应不佳，许多人患有难治性 cGVHD。此外，严重缺乏治疗。有关决定接受 cGVHD 治疗的个体患者临床反应的信息。我们对人类 cGVHD 发病机制的理解取得了突破，并优先考虑下一代治疗的过程中，我们必须（1）准确地定义最终在患者体内活跃的免疫途径。发展 cGVHD 并 (2) 确定 cGVHD 治疗方案成功和失败的机制为了实现这些目标，该项目将完成以下具体任务。在目标 1 中，我们将在第 +100 天确定 cGVHD 的风险分配免疫特征。确定 cGVHD 患者治疗反应性与耐药性免疫特征的演变。目标 3 我们将根据完整的轨迹分析来研究 Tregs 基因修饰的影响对低剂量 IL-2 有反应者与无反应者进行比较，以创建优化的细胞疗法来控制通过实现这些目标，该项目有望识别预测的分子网络。 cGVHD，以及与 cGVHD 疗法的反应或耐药相关的那些，从而为该疾病成功预防和治疗策略的新时代。