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Immune Targeting of non-Hodgkin Lymphoma through Integrative Antigen Presentation Profiling

通过综合抗原呈递分析对非霍奇金淋巴瘤进行免疫靶向

基本信息

批准号：
10098002
负责人：
Michael Siavash Khodadoust
金额：
$ 17.35万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10098002
关键词：
Address Advisory Committees Affect Antigen Presentation Antigens Autologous B-Lymphocytes CD4 Positive T Lymphocytes Characteristics Chronic Lymphocytic Leukemia Clinical Clinical Trials Crystallization DEK gene Data Development Development Plans Diagnosis Doctor of Philosophy Environment Event Follicular Lymphoma Foundations Future Genes Genetic Engineering Genomics Goals Health Histocompatibility Antigens Class II Histology Immune Immune Targeting Immune response Immune system Immunoglobulin Somatic Hypermutation Immunoglobulin Variable Region Immunoglobulins Immunology Immunotherapy Knowledge Life Ligands Lymphoma Lymphoma cell Major Histocompatibility Complex Malignant Neoplasms Mantle Cell Lymphoma Mediating Mentors Mentorship Michigan Mission Nature Non-Hodgkin&apos s Lymphoma Oncogenic Oncology Organism Patients Pattern Peptides Physicians Proteomics Recording of previous events Research Scientist Seminal Series Sezary Syndrome Solid Specificity System T cell receptor repertoire sequencing T cell response T cell therapy T-Cell Receptor T-Lymphocyte Testing Training Training Programs Transgenic Organisms Translating Translations Tumor Antigens United States National Institutes of Health Universities Update V(D)J Recombination Woman Work base cancer cell career career development cytotoxicity design disability engineered T cells exome sequencing improved innovation instructor large cell Diffuse non-Hodgkin&apos s lymphoma medical schools men neoantigens next generation sequencing non-Hodgkin&apos s lymphoma patients novel novel strategies public health relevance response single cell analysis targeted treatment translational study tumor variable region gene

项目摘要

SUMMARY/ABSTRACT: Dr. Michael Khodadoust is an Instructor in Oncology at Stanford University. He and his mentors, Drs. Ash Alizadeh and Ronald Levy, have developed a comprehensive career development plan designed to prepare him for his long term goal of an independent career in translational studies of immunotherapy in non-Hodgkin lymphoma (NHL). The Applicant: Dr. Khodadoust has consistently pursued his goal of an academic career in translational oncology. He completed his MD/PhD training in Immunology at the University of Michigan Medical School discovering oncogenic functions of the DEK gene. More recently, Dr. Khodadoust applied a novel approach integrating genomic and proteomic data to profile mantle cell lymphoma (MCL) tumor antigens, revealing that the lymphoma immunoglobulin is a key antigen that is almost exclusively presented by class II MHC. Mentorship Environment and Career Development Plan: Both mentors are practicing physician-scientists with a history of providing seminal contributions to the understanding and treatment of NHL. Training will be focused in developing a foundation in computational aspects of immunology and enhancing prior immunology training. There will be specific practical training in T cell engineering with transgenic T cell receptors as a means to translate antigen profiling results into future clinical therapies. The plan incorporates didactic courses, seminar series, and participation in formal training programs, both internal and external to Stanford University. A distinguished advisory committee consisting of Drs. Mark Davis, Crystal Mackall, and Philip Greenberg will closely assist in training and mentorship. Research: The key antigens that determine immune recognition of NHL remain unknown. We have developed an innovative strategy to uncover novel tumor antigens, incorporating genomic and proteomic profiling to identify peptides presented by the major histocompatibility complex (MHC) of cancer cells. This approach was designed to specifically include patient-specific antigens including neoantigens. In preliminary work with MCL, we have discovered that the only presented neoantigens were derived from unique lymphoma immunoglobulin VDJ rearrangements and somatic hypermutation events. In the first aim, we now propose to extend this analysis to other more common subtypes of NHL including diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, marginal zone lymphoma, and Sezary syndrome. In the second aim, we will focus on identifying T cell receptors (TCRs) specific for common NHL shared immunoglobulin-derived antigens. These lymphoma-specific TCRs will be delivered into patient T cells and tested for cytolytic activity against primary lymphoma cells as a proof of principle for future T cell-based therapies targeting the lymphoma immunoglobulin.

概要/摘要：Michael Khodadoust博士是斯坦福大学肿瘤学讲师。他和他的导师阿什·阿里扎德博士和罗纳德·利维博士制定了一个全面的职业发展计划旨在为他在免疫治疗转化研究中的独立职业生涯的长期目标做好准备非霍奇金淋巴瘤（NHL）。申请人：Khodadoust博士一直追求他的翻译学术生涯的目标。肿瘤学他在密歇根大学医学院完成了免疫学的医学博士/博士培训发现DEK基因的致癌功能。最近，Khodadoust博士应用了一种新的方法，整合基因组和蛋白质组学数据以分析套细胞淋巴瘤（MCL）肿瘤抗原，揭示了淋巴瘤免疫球蛋白是几乎完全由II类MHC呈递的关键抗原。导师环境和职业发展计划：两位导师都是执业医师-科学家为NHL的理解和治疗做出了开创性贡献。培训将专注于发展免疫学的计算方面的基础，并提高先前的免疫学训练将有具体的实践训练，在T细胞工程与转基因T细胞受体为手段将抗原分析结果转化为未来的临床治疗。该计划包括教学课程、研讨会系列，并参加正式的培训计划，内部和外部的斯坦福大学。一由Mark Davis博士、Crystal Mackall博士和Philip Greenberg博士组成的杰出咨询委员会将密切协助培训和指导。研究：决定NHL免疫识别的关键抗原仍然未知。我们已经开发一种发现新型肿瘤抗原的创新策略，结合基因组和蛋白质组学分析，由癌细胞的主要组织相容性复合体（MHC）呈递的肽。这种方法的目的是具体包括患者特异性抗原，包括新抗原。在与MCL的初步工作中，我们有发现唯一呈递的新抗原来源于独特的淋巴瘤免疫球蛋白VDJ 重排和体细胞超突变事件。在第一个目标中，我们现在建议将这种分析扩展到其他更常见的NHL亚型包括弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴瘤、慢性淋巴细胞性白血病和慢性淋巴细胞性白血病。淋巴细胞白血病、边缘区淋巴瘤和塞扎里综合征。在第二个目标中，我们将重点关注鉴定对常见NHL共有免疫球蛋白衍生抗原特异的T细胞受体（TCR）。这些淋巴瘤特异性TCR将被递送到患者T细胞中，并测试针对原发性T细胞的细胞溶解活性。淋巴瘤细胞作为未来靶向淋巴瘤免疫球蛋白的基于T细胞的疗法的原理证明。