Targeting epigenetic regulation via Bromodomain and Extraterminal (BET) domain inhibition for treatment of GVHD

通过 Bromodomain 和 Extraterminal (BET) 结构域抑制靶向表观遗传调控治疗 GVHD

基本信息

批准号：
10383705
负责人：
Hannah Choe
金额：
$ 41.5万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-05 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10383705
关键词：
Acute Graft Versus Host Disease Adrenal Cortex Hormones Affect Allogenic BCL2 gene Benzodiazepines Biological Biology Bromodomain CD80 gene CD86 gene Calcineurin Cell Cycle Cell Survival Cell physiology Clinical Clinical Research Clinical Trials Combined Modality Therapy Complication Correlative Study Cytokine Receptors Data Dendritic Cells Development Disease Drug Kinetics Epigenetic Process FDA approved Future Genes Genetic Transcription Goals Hematological Disease Histone Acetylation Homologous Transplantation Human Immunobiology In Vitro Individual Infection Inflammation Inflammation Mediators Inflammatory Interferon Type II Interleukin-17 Interleukin-2 Interleukin-6 Investigation JAK1 gene Life Mediating Mediator of activation protein Molecular Mus NF-kappa B Pathogenesis Pathogenicity Pathway interactions Patient-Focused Outcomes Patients Phase Phenotype Pre-Clinical Model Proteins Quality of life Reader Refractory Regulatory T-Lymphocyte Research Risk Safety Severity of illness Stem cell transplant Steroid therapy Steroids Structure T cell response T-Cell Proliferation T-Lymphocyte T-Lymphocyte Subsets TNF gene TNFRSF5 gene TNFSF5 gene Testing Tissues Toxic effect Transcriptional Regulation Translating Transplant Recipients chromatin modification clinical efficacy combat combinatorial curative treatments cytokine cytotoxic CD8 T cells design disorder prevention effective therapy effector T cell epigenetic regulation experimental study graft vs leukemia effect immune reconstitution improved in vivo inhibitor innovation mortality mouse model novel novel therapeutics pre-clinical pre-clinical research preclinical study prevent response safety and feasibility scaffold small molecule inhibitor success synergism translational approach treatment duration treatment response

项目摘要

Abstract Acute Graft-versus-Host Disease (aGVHD) occurs due to donor T cell alloreactivity against host tissues and is the major cause of non-relapse mortality after allogeneic stem cell transplantation (alloSCT). Approximately 50% of patients are not responsive to front-line corticosteroid therapy and deemed “steroid-refractory” with limited to no effective standard therapies. Our long-term research goal is to identify and evaluate innovative approaches to improve patient outcomes by preventing and/or abrogating aGVHD toxicity post-alloSCT. The proposed research presents pioneering clinical and translational approaches to target epigenetic regulation of inflammatory mediators via Bromodomain and Extraterminal (BET) domain inhibition using novel non- benzodiazepine structured PLX (51107 and 2853) to prevent and mitigate aGVHD. PLX boasts improved pharmacokinetic and tolerability profiles to benzodiazepine-scaffolded BET inhibitors. We observed that BET inhibition with PLX results in potent suppression of T cell proliferation and pro-inflammatory cytokine secretion of IFN-g, IL-6, and TNF-α without affecting T cell viability. Our data also demonstrate that BET inhibition with PLX significantly downregulates transcription of T cell costimulatory genes, major inflammatory cytokines, and cell-cycle regulators. Importantly, we identified that BET inhibition decreases T cell proliferation and dampens inflammation independent of STAT-1. Thus, we targeted JAK/STAT blockade with the recently FDA approved JAK1/2 inhibitor ruxolitinib and observed synergistic effects of dual BET and JAK1/2 inhibition on T cell proliferation. We hypothesize that BET inhibition with PLX is a feasible, effective strategy to mitigate T cell mediated aGVHD inflammation as a single agent. Further, we propose preclinical analyses to assess the synergistic mechanisms and tolerability of dual BET/JAK1/2 inhibition. Aim 1 of the proposed research tests our hypothesis in a Phase 1b/2 proof-of-principle clinical trial for patients with steroid-refractory aGVHD with single agent PLX51107. Correlative studies are designed to assess 1) response to therapy and 2) immune reconstitution of T cell subsets. In Aim 2, we will use preclinical models of aGVHD to test the hypothesis that BET inhibition results in improvement in aGVHD survival by downregulating Th1 and Th17 pathogenic T cell responses while maintaining Treg mediated tolerance. We observed a very strong reduction in expression of Th1/Th17 pro-inflammatory genes such as IFN- g, IL-17 and IL-2 as well as co-stimulatory molecule CD40L with PLX treated T cells in vitro. We propose to analyze the effects of PLX on individual T cell subsets and their implications in aGVHD pathogenesis in vivo. Aim 3 will 1) test the hypothesis that dual BET and JAK1/2 inhibition will reduce GVHD and prolong duration of treatment response; and 2) assess the effects of combination therapy on Treg and effector T cell function. These experiments will determine the future applicability of T cell subset directed therapy for aGVHD as well as inform the development of future clinical trials combining BET and JAK1/2 inhibition for aGVHD prevention or treatment indications.

抽象的急性移植抗宿主病（AGVHD）是由于供体T细胞针对宿主组织的，IS 同种异体干细胞移植后非释放死亡率的主要原因（AlloSCT）。大约 50％的患者对前线皮质类固醇治疗没有反应，并被认为是“类固醇难治性” 仅限于没有有效的标准疗法。我们的长期研究目标是识别和评估创新通过预防后，通过预防和/或消除AGVHD毒性来改善患者预后的方法。这拟议的研究提出了开创性的临床和翻译方法，以靶向表观遗传调节使用新型非 - 苯二氮卓类结构化PLX（51107和2853）可预防和减轻AGVHD。 PLX拥有改善对苯二氮卓类药物抑制剂的药代动力学和耐受性。我们观察到了下注抑制PLX会导致潜在抑制T细胞增殖和促炎性细胞因子分泌不影响T细胞活力的IFN-G，IL-6和TNF-α。我们的数据还表明，抑制 PLX显着下调了T细胞共刺激基因的转录，主要的炎症细胞因子和细胞周期调节剂。重要的是，我们确定下注抑制会下降T细胞增殖并衰减炎症独立于Stat-1。那就是我们以最近批准的FDA为目标 JAK1/2抑制剂r氧替尼，并观察到双重BET和JAK1/2抑制对T细胞的协同作用增殖。我们假设对PLX的抑制是一种减轻T细胞的可行，有效的策略介导的AGVHD炎症作为单一药物。此外，我们提出了临床前分析以评估双重BET/JAK1/2抑制的协同机制和耐受性。目标1的目标研究测试我们在1B/2期的原则证明临床试验中的假设单代理PLX51107。相关研究旨在评估1）对治疗的反应和2）免疫 T细胞子集的重构。在AIM 2中，我们将使用AGVHD的临床前模型来检验以下假设。 BET抑制作用通过下调TH1和TH17致病性T细胞来改善AGVHD存活率在保持Treg介导的耐受性的同时做出反应。我们观察到表达的表达非常大大降低 Th1/Th17促炎基因，例如IFN-G，IL-17和IL-2以及共刺激分子CD40L 与PLX处理的T细胞体外。我们建议分析PLX对单个T细胞亚群及其它们的影响体内AGVHD发病机理的含义。 AIM 3将1）测试双重赌注和JAK1/2的假设抑制作用将减少GVHD并延长治疗反应的持续时间； 2）评估 Treg和效应T细胞功能的联合疗法。这些实验将决定未来 T细胞子集的定向疗法适用于AGVHD，并为未来临床的发展提供了信息结合BET和JAK1/2抑制AGVHD预防或治疗适应症的试验。