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：
10083639
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/10083639
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 I/II Clinical Trial 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 antigen-specific T cells biobank career development clinical investigation clinical translation conditioning design disorder later incidence prevention fighting graft vs host disease graft vs leukemia effect healthy volunteer high risk improved innate immune function innovation laboratory experience leukemia leukemia relapse 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.

项目摘要 /摘要该提案的核心目标是a）支持在清理研究中获得高级培训的收购与进行有关的方法，道德原则和人类免疫学对同种异体造血干细胞移植（HCT）和b）进行研究了解生物学指导的HCT导演的概念证明试验，以减少急性髓样的复发白血病（AML）我将在五个事业发展中实现这些目标活动：1）作为直接从您直接翻译的临床研究的有指导的主要研究者实验室2）获得深入的实验室换档人类同种异体HCT免疫反应 3）将免疫学的研究生课程与临床科学硕士结合在一起研究设计和统计分析（CRDSA）。同种异体HCT代表了通知血液学的唯一治愈方法 AML。淋巴细胞。 HCT。淋巴细胞（DLI）受到主要的毒性，原发性移植物抗宿主病（GVHD）的限制。对正常和恶性宿主组织的共同免疫力在将GVL与 GVHD要克服此障碍，供体T细胞必须“启动”以更具体地回应白血病未直接保留的抗原，而是由专业抗原呈现细胞呈现（APC），一种称为交叉压力的过程。人类（BDCA3+ DC）中的对应物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，我们证明了CD8α+DCS的交叉呈现促进了GVL 加重GVHD的反应。在特定目标1中的介绍和后续的GVL。进入概念验证阶段I/II临床试验，以减少高风险患者AML AML HCT的复发为了复发。减少复发而不增加特定目标中GVHD的频率或严重性。 Pegypated IFN-α对白血病抗原的交叉呈影响对BDCA3+ DC的影响。假设增强交叉压力将导致白血病抗原特异性T细胞增加回答。该提案反映了我先前研究的逻辑扩展，并遵循了职业生涯的完善计划开发。安全增加GVL反应的机制，这将提供直接临床的证据从长凳上翻译，并提供了一种新方法，用于恢复HCT后的保护性免疫。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Type 1 interferon to prevent leukemia relapse after allogeneic transplantation.

DOI：
10.1182/bloodadvances.2021004908
发表时间：
2021-12-14
期刊：
BLOOD ADVANCES
影响因子：
7.5
作者：
Magenau, John M.;Peltier, Dan;Riwes, Mary;Pawarode, Attaphol;Parkin, Brian;Braun, Thomas;Anand, Sarah;Ghosh, Monalisa;Maciejewski, John;Yanik, Gregory;Choi, Sung Won;Talpaz, Moshe;Reddy, Pavan
通讯作者：
Reddy, Pavan

Immunopathology and biology-based treatment of steroid-refractory graft-versus-host disease