Targeting T-cell costimulation and cytokine activation to prevent GVHD and preserve GVL

靶向 T 细胞共刺激和细胞因子激活以预防 GVHD 并保留 GVL

• 批准号: 9918445
• 负责人: Brian C Betts
• 金额: $ 40.92万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918445
• 关键词: Acute Graft Versus Host Disease; Alloantigen; Allogenic; Allografting; Antitumor Response; Biological; CD28 gene; CD4 Positive T Lymphocytes; Calcineurin inhibitor; Cell physiology; Cells; Clinical Trials; Comb animal structure; Complication; Cytokine Activation; Cytotoxic T-Lymphocytes; Data; Development; Dose; Drug Combinations; Effector Cell; Elements; Exposure to; FRAP1 gene; Fc Receptor; Future; Goals; Human; Immune; Immunosuppression; Impairment; Infection; Inflammatory; Interleukin 6 Receptor; Interleukin-6; Investigation; JAK2 gene; Life; Longevity; Mediating; Medicine; Molecular; Mus; Myelofibrosis; Outcome; PPP3CA gene; Pathogenicity; Pathway interactions; Phase; Phosphorylation; Phosphotransferases; Prevention trial; Prophylactic treatment; Receptor Activation; Recovery; Regimen; Regulatory T-Lymphocyte; Research; Rodent; STAT3 gene; Signal Transduction; Signaling Molecule; Sirolimus; Stat5 protein; Stem cell transplant; T cell response; T-Cell Receptor; T-Lymphocyte; Tacrolimus; Testing; Translations; Transplant Recipients; Transplantation; allograft rejection; aurora kinase; base; cancer cell; clinical efficacy; design; disorder prevention; experimental study; graft vs host disease; graft vs leukemia effect; hematopoietic cell transplantation; improved; improved outcome; inhibitor/antagonist; innovation; mTOR Inhibitor; mTOR inhibition; mortality; novel; novel strategies; preservation; prevent; response; skin allograft; Acute Graft Versus Host Disease; Alloantigen; Allogenic; Allografting; Antitumor Response; Biological; CD28 gene; CD4 Positive T Lymphocytes; Calcineurin inhibitor; Cell physiology; Cells; Clinical Trials; Comb animal structure; Complication; Cytokine Activation; Cytotoxic T-Lymphocytes; Data; Development; Dose; Drug Combinations; Effector Cell; Elements; Exposure to; FRAP1 gene; Fc Receptor; Future; Goals; Human; Immune; Immunosuppression; Impairment; Infection; Inflammatory; Interleukin 6 Receptor; Interleukin-6; Investigation; JAK2 gene; Life; Longevity; Mediating; Medicine; Molecular; Mus; Myelofibrosis; Outcome; PPP3CA gene; Pathogenicity; Pathway interactions; Phase; Phosphorylation; Phosphotransferases; Prevention trial; Prophylactic treatment; Receptor Activation; Recovery; Regimen; Regulatory T-Lymphocyte; Research; Rodent; STAT3 gene; Signal Transduction; Signaling Molecule; Sirolimus; Stat5 protein; Stem cell transplant; T cell response; T-Cell Receptor; T-Lymphocyte; Tacrolimus; Testing; Translations; Transplant Recipients; Transplantation; allograft rejection; aurora kinase; base; cancer cell; clinical efficacy; design; disorder prevention; experimental study; graft vs host disease; graft vs leukemia effect; hematopoietic cell transplantation; improved; improved outcome; inhibitor/antagonist; innovation; mTOR Inhibitor; mTOR inhibition; mortality; novel; novel strategies; preservation; prevent; response; skin allograft

ABSTRACT Graft-versus-host disease (GVHD) is a leading cause of non-relapse mortality after allogeneic hematopoietic cell transplantation (alloHCT). Current GVHD prophylaxis relies on broadly suppressive tacrolimus-based combinations that fail to tolerize donor T-cells. Tacrolimus inhibits T-cell receptor (TCR) activation and impairs regulatory T-cell (Treg) longevity and function. Rather than targeting the TCR, the novel approach tested in this application is concurrent blockade of T-cell costimulation and cytokine activation as a strategy to spare Tregs, prevent GVHD, and maintain graft-versus-leukemia (GVL). CD28 costimulation of T-cells requires signal transduction by mTOR and Aurora kinase, where inhibiting either molecule ameliorates GVHD in rodents. The IL-6 receptor directs JAK2 to phosphorylate STAT3, which polarizes pathogenic Th1 and Th17 development over beneficial Tregs. We observed that STAT3 activity is increased in alloHCT recipients who later develop acute GVHD. Blockade of JAK2 or STAT3 also reduces murine GVHD. Our data support the concept that dual inhibition of CD28 and IL-6 activity is synergistic and offers durable GVHD prevention with intact GVL. Aim 1 of this application will test this hypothesis in a proof-of-principle clinical trial by combing pacritinib with sirolimus-based immune suppression to respectively target JAK2 and mTOR signaling and reduce GVHD. Aims 2 and 3 will test the hypotheses that neutralization of downstream signaling molecules directed by CD28 and IL-6 will yield distinct immune outcomes and collectively more complete control over donor T-cells. Unlike JAK2, STAT3 molecularly counteracts Treg development. We provide evidence that JAK2 blockade permits natural Treg development, while STAT3 inhibition increases inducible Tregs (iTreg). In Aim 2, we will investigate whether STAT3/mTOR inhibition is better than JAK2/mTOR inhibition in reducing GVHD in mice by enhancing iTreg differentiation. We provide evidence that inhibition of Aurora kinase significantly increases iTreg suppressive potency. In Aim 3, we will determine whether targeting STAT3/Aurora is better than JAK2/Aurora to prevent GVHD by increasing both iTreg differentiation and function. These experiments will direct future translation and development of tacrolimus-free GVHD prophylaxis regimens. Our long-term goal is to develop selective immune suppression strategies that effectively prevent GVHD and maintain essential T-cell responses needed to preserve GVL.

抽象的 移植物与宿主病（GVHD）是同种异体造血后非释放死亡率的主要原因 细胞移植（alloHCT）。当前的GVHD预防依赖于基于他的克莫司的广泛抑制 无法容忍供体T细胞的组合。他克莫司抑制T细胞受体（TCR）激活并损害 调节性T细胞（Treg）寿命和功能。新颖的方法不是针对TCR，而是在 该应用程序同时阻碍了T细胞共刺激和细胞因子激活作为备用的策略 Tregs，预防GVHD并维持移植物与白血病（GVL）。 CD28 T细胞的共刺激需要 MTOR和Aurora激酶的信号转导，其中任何一种分子都可以改善GVHD 啮齿动物。 IL-6受体将JAK2引导到磷酸化STAT3，该磷酸化stat3使致病性TH1和TH17极化 对有益的Treg的发展。我们观察到AlloHCT接受者的STAT3活性增加了 后来发展急性GVHD。 JAK2或STAT3的封锁也减少了Murine GVHD。我们的数据支持 双重抑制CD28和IL-6活性的概念是协同的，并提供了持久的GVHD预防 完整的GVL。本应用的目标1将通过梳理在原则临床试验中检验该假设 基于西罗莫司的parc依尼分别靶向JAK2和MTOR信号传导以及 减少GVHD。目标2和3将检验下游信号分子中和的假设 由CD28和IL-6指导的 供体T细胞。与JAK2不同，STAT3分子可以抵消Treg的发展。我们提供证据表明 JAK2阻断允许自然的Treg发育，而STAT3抑制增加了诱导型Treg（ITREG）。在 AIM 2，我们将研究STAT3/mTOR抑制是否优于JAK2/mTOR抑制 通过增强ITREG分化，小鼠中的GVHD。我们提供了抑制极光激酶的证据 显着增加ITREG抑制效力。在AIM 3中，我们将确定是否针对STAT3/Aurora 通过增加ITREG分化和功能来预防GVHD，比JAK2/Aurora更好。这些 实验将指导未来的无克拉略曲霉GVHD预防疗法的翻译和发展。我们的 长期目标是制定有效防止GVHD和的选择性免疫抑制策略 保持保留GVL所需的基本T细胞响应。