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

靶向抗原交叉呈递以增强同种异体移植后的抗白血病反应

基本信息

批准号：
9242182
负责人：
John Martin Magenau
金额：
$ 19.66万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9242182
关键词：
Acute Myelocytic Leukemia Adopted Allogenic Antigen Targeting Antigen-Presenting Cells Antigens Biology Cells Clinic Clinical Research Clinical Trials Cross Presentation Data Development Effectiveness Environment Ethics Experimental Models FDA approved Fostering Frequencies Generations Goals Hematologic Neoplasms Hematological Disease Hematopoietic Hematopoietic Neoplasms Hematopoietic Stem Cell Transplantation High Dose Chemotherapy Homologous Transplantation Human Immune Immune response Immunity Immunology Immunotherapeutic agent Infection Interferon-alpha Interferons Investigation Knowledge Laboratories Life Lymphocyte Malignant - descriptor Malignant Neoplasms Master of Science Mentors Mentorship Methodology Modeling Molds Monitor Mus Patients Phase Phase I/II Trial Procedures Process Recurrence Relapse Research Research Design Research Methodology Research Personnel Research Training Sampling Sampling Studies Severities Statistical Data Interpretation Stem cell transplant Structure T cell response T-Lymphocyte Techniques Testing Time Tissues Toxic effect Training Translating Translations Transplantation Immunology Viral biobank career development clinical investigation clinical translation conditioning design disorder later incidence prevention fighting graft vs host disease healthy volunteer high risk improved innate immune function innovation laboratory experience leukemia mortality novel strategies patient oriented pre-clinical preclinical study relapse risk response responsible research conduct skills

项目摘要

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.

项目概要/摘要该提案的中心目标是 a) 支持获得临床研究高级培训方法论、伦理原则和人类免疫学，因为它涉及以患者为导向异基因造血干细胞移植（HCT）的研究和b）大力追求深入了解生物学指导的 HCT 概念验证试验旨在减少急性髓系疾病复发我将通过完成以下职业发展在五年内实现这些目标。活动：1) 担任直接从《临床研究》翻译的临床研究的指导主要研究者实验室 2) 获得监测人类同种异体 HCT 免疫反应的深入实验室培训 3) 完成免疫学研究生课程以及临床理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疾病的唯一治疗方法，包括 AML。HCT 通过供体的移植物抗白血病（GVL）反应提供有效的免疫治疗效果。尽管具有巨大的潜力，但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（调理）或供体给药来减少复发。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）。针对正常和恶性宿主组织的共同免疫导致了将 GVL 与为了克服这一障碍，供体 T 细胞必须“做好准备”，以对白血病做出更特异性的反应。不直接呈递而是由专业抗原呈递细胞呈递的抗原（APC），在小鼠（CD8α+ DC）及其中发现的一种称为交叉呈递的过程。人类的 DC 细胞（BDCA3+ DC）对于启动白血病抗原特异性 T 细胞反应至关重要。 HCT 的临床前研究，我们证明增强 CD8α+DC 上的交叉呈递可促进 GVL 此外，1 型干扰素 (IFN-α) 能够增强交叉作用。在 HCT 模型中的演示和后续 GVL，这些概念被直接翻译。一项概念验证 I/II 期临床试验，以减少高危患者 HCT 后 AML 的复发我们将测试 FDA 批准的聚乙二醇化 IFN-α 药物治疗是否会复发的假设。在不增加 GVHD 发生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 IFN-α 对 BDCA3+ DC 上白血病抗原交叉呈递的影响。假设增强交叉呈递会导致白血病抗原特异性 T 细胞增加回应。该提案反映了我之前研究的逻辑延伸，并遵循精心制定的职业计划这是第一项专门针对抗原交叉呈递而设计的 HCT 研究。如果成功，这将提供直接临床证据。实验室的翻译并提供了一种在 HCT 后恢复保护性免疫力的新方法。