Targeting antigen cross-presentation to enhance anti-leukemic responses after allogeneic transplantation

项目摘要/摘要 这项提议的中心目标是：a)支持获得临床研究方面的高级培训 方法论、伦理原则和人类免疫学，因为它与以患者为中心的 研究异基因造血干细胞移植(HCT)和b)大力追求深度 关于减少急性髓系白血病复发的HCT生物引导概念验证试验的认识 白血病(AML)。我将在五年内通过完成以下职业发展来实现这些目标 活动：1)担任临床研究的指导原则研究员，该研究直接从 实验室2)在监测人类同种异体红细胞免疫反应方面获得深入的实验室培训 3)完成免疫学研究生课程和临床理学硕士学位 研究设计与统计分析(CRDSA) 异基因血细胞移植是治疗几种恶性血液病的唯一方法，包括 AML。HCT通过供者的移植物抗白血病(GVL)反应提供强大的免疫治疗效果 淋巴细胞。尽管有这种巨大的潜力，复发仍然是提高术后存活率的主要障碍。 HCT。通过增加大剂量化疗(调理)或供体管理来减少复发 淋巴细胞(DLI)受到主要毒性的限制，主要是移植物抗宿主病(GVHD)。 对正常和恶性宿主组织的共同免疫力是将GVL与 GVHD。为了克服这一障碍，捐赠者的T细胞必须做好准备，以更特异地应对白血病 不是直接提呈，而是由专业的抗原提呈细胞提呈的抗原 (APC)，这一过程称为交叉演示。小鼠体内发现的特异性APC(CD8α+DC)及其功能 人类同源细胞(BDCA3+DC)在启动白血病抗原特异性T细胞反应中起关键作用。在……里面 巨噬细胞移植的临床前研究，我们证实增强CD8CD8+α+DC的交叉呈递促进移植物抗宿主病 在不加重GVHD的情况下缓解。此外，1型干扰素(干扰素-α)能够增强交叉反应。 在HCT模型中的呈现和随后的GVL。在具体目标1中，这些概念被直接翻译 一项概念验证性I/II期临床试验，以减少高危患者HCT后AML的复发 治疗旧病复发。我们将检验这样一种假设，即用FDA批准的药物聚乙二醇化干扰素-α治疗将 在不增加移植物抗宿主病的频率或严重程度的情况下减少复发。在具体目标2中，我们确定了 聚乙二醇化干扰素-α对BDCA3+DC交叉提呈白血病抗原的影响我们将测试 增强交叉呈现将导致白血病抗原特异性T细胞增加的假说 回应。 这项建议反映了我先前研究的合乎逻辑的扩展，并遵循了一个精心设计的职业规划 发展。这是第一项专门针对抗原交叉呈递而设计的HCT研究 安全增加GVL反应的机制。如果成功，这将提供直接的临床证据。 并为恢复HCT后的保护性免疫提供了一种新的方法。

PROJECT SUMMARY / ABSTRACT The central goals of this proposal are a) to support the acquisition of advanced training in clinical research methodologies, ethical principles and human immunology as it pertains to conducting patient-oriented investigations in allogeneic hematopoietic stem cell transplantation (HCT) and b) to vigorously pursue a deep understanding of biology guided proof-of-concept trials in HCT directed at reducing relapse in Acute Myeloid Leukemia (AML). I will achieve these goals within five years by completing the following career development activities: 1) serving as a mentored principle investigator on a clinical study directly translated from the laboratory 2) acquiring in-depth laboratory training in monitoring human allogeneic HCT immune responses and 3) completing graduate coursework in immunology together with a Master's of Science in Clinical Research Design and Statistical Analysis (CRDSA). Allogeneic HCT represents the lone curative approach for several malignant hematologic diseases including AML. HCT delivers potent immunotherapeutic effects through graft-versus-leukemia (GVL) responses of donor lymphocytes. Despite this great potential, relapse remains the major impediment to improving survival after HCT. Reducing relapse by increasing high dose chemotherapy (conditioning) or administration of donor lymphocytes (DLI) are limited by major toxicity, primarily graft-versus-host disease (GVHD). Shared immunity against normal and malignant host tissues underlies the difficulty in separating GVL from GVHD. To overcome this barrier, donor T cells must be `primed' to more specifically respond to leukemia antigens that are not presented directly but instead presented by the professional antigen presenting cells (APCs), a process known as cross-presentation. Specialized APCs found in mice (CD8α+ DCs) and their counterparts in humans (BDCA3+ DCs), are crucial for initiating leukemia antigen specific T cell responses. In preclinical studies of HCT, we demonstrate enhancing cross-presentation on CD8α+DCs promotes GVL responses without aggravating GVHD. Moreover, type 1 interferon (IFN-α) is capable of enhancing cross- presentation and subsequent GVL in models of HCT. In Specific Aim 1, these concepts are directly translated to a proof-of-concept phase I/II clinical trial to reduce the recurrence of AML after HCT in patients at high risk for relapse. We will test the hypothesis that treatment with the FDA approved agent pegylated IFN-α will reduce relapse without increasing the frequency or severity of GVHD. In Specific Aim 2, we determine the impact of pegylated IFN-α on cross-presentation of leukemia antigens on BDCA3+ DCs. We will test the hypothesis that enhancing cross-presentation will result in increases in leukemia antigen specific T cell responses. This proposal reflects a logical extension of my prior research and follows a well laid out plan for career development. It is the first HCT study specifically designed to target antigen cross-presentation as a mechanism for safely increasing GVL responses. If successful, this will provide evidence of direct clinical translation from the bench and provide a new approach for restoring protective immunity following HCT.