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

项目总结/摘要 该提案的中心目标是：a）支持获得临床研究方面的高级培训 方法，伦理原则和人类免疫学，因为它涉及到进行以病人为导向的 异基因造血干细胞移植（HCT）和B）的研究，以大力追求深入的 理解HCT中旨在减少急性髓系白血病复发的生物学指导的概念验证试验 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）担任指导的临床研究的主要研究者，直接翻译自 实验室2）获得监测人类同种异体HCT免疫应答的深入实验室培训 以及3）完成免疫学研究生课程以及临床科学硕士学位 研究设计和统计分析（CRDSA）。 同种异体HCT代表了几种恶性血液病的唯一治愈方法，包括 急性髓细胞白血病HCT通过供体的移植物抗白血病（GVL）反应提供有效的免疫抑制作用 淋巴细胞尽管有这种巨大的潜力，复发仍然是提高术后生存率的主要障碍。 HCT。通过增加高剂量化疗（预处理）或供体给药减少复发 淋巴细胞（DLI）的主要毒性主要是移植物抗宿主病（GVHD）。 针对正常和恶性宿主组织的共同免疫是难以将GVL与 GVHD。为了克服这一障碍，供体T细胞必须被“激发”以更特异地对白血病作出反应 不直接呈递而是由专职抗原呈递细胞呈递的抗原 （APC），这一过程被称为交叉呈递。小鼠中发现的特异性APC（CD 8 α+ DC）及其 在人类中的对应物（BDCA 3 + DC）对于启动白血病抗原特异性T细胞应答至关重要。在 HCT的临床前研究表明，增强CD 8 α+DCs的交叉呈递可促进GVL 而不会加重GVHD。此外，1型干扰素（IFN-α）能够增强交叉- 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为 一项旨在减少高危患者HCT后AML复发的概念验证I/II期临床试验 治疗复发我们将检验用FDA批准的聚乙二醇化IFN-α治疗将 减少复发而不增加GVHD的频率或严重程度。在具体目标2中，我们确定 聚乙二醇化IFN-α对BDCA 3 + DC上白血病抗原交叉呈递的影响我们将测试 增强交叉呈递将导致白血病抗原特异性T细胞增加假说 应答 这个建议反映了我先前研究的逻辑延伸，并遵循一个良好的职业规划 发展这是第一项专门设计用于靶向抗原交叉呈递的HCT研究， 安全增加GVL反应的机制。如果成功，这将提供直接临床证据， 从实验室翻译，并提供了一种新的方法，用于恢复HCT后的保护性免疫力。

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.