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

• 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
• 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

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临床应答的T细胞介导因子 摘要： 慢性移植物抗宿主病（cGVHD）是移植后发病和晚期死亡的主要原因。 造血干细胞移植（HCT）。虽然多种先天性和适应性免疫细胞群 由于供体T细胞参与了cGVHD的病理生理过程，因此供体T细胞在所有阶段都参与了cGVHD，无论是通过它们的直接作用， 影响，或通过它们对其他细胞群体的影响。然而，尽管有详细的信息， 从小鼠模型中控制cGVHD的机制，以及几种新的临床 在治疗中，完全缓解（CR）率仍然很低：大多数患者仅表现出部分缓解。 对治疗有反应，许多人患有难治性cGVHD。此外，严重缺乏 关于决定接受cGVHD治疗的个体患者的临床应答的因素的信息。使 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 我们必须（1）准确定义患者体内的免疫途径， 发展cGVHD和（2）确定cGVHD治疗方案成功和失败的机制 在个体患者的水平上。为了实现这些目标，本项目将完成以下具体工作： 目标。在目标1中，我们将确定第+100天cGVHD的风险分配免疫特征。在目标2中，我们 确定cGVHD患者中治疗应答与耐药免疫谱的演变。在 目的3：我们将根据从1999年至2000年的完整轨迹分析， 对低剂量IL-2的应答者与非应答者，以创建优化的细胞治疗剂来控制 cGVHD。通过实现这些目标，该项目有望确定预测的分子网络 cGVHD，以及那些与cGVHD治疗的反应或抗性相关的，从而为治疗cGVHD铺平了道路。 成功预防和治疗这种疾病的新时代。