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Functional epigenomics of transgenic cellular immunotherapies for cancer

癌症转基因细胞免疫疗法的功能表观基因组学

基本信息

批准号：
10558728
负责人：
Theodore Scott Nowicki
金额：
$ 18.19万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-10 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10558728
关键词：
ATAC-seq Advisory Committees Area Bioinformatics Biological Biological Assay California Cell Therapy Cell physiology Cells Cellular immunotherapy Characteristics Chromatin Classification Clinical Committee Members Computational Biology Cytometry Cytosine DNA DNA Methylation DNA Sequence DNA sequencing Functional disorder Gene Expression Gene Expression Profile Generations Genes Genetic Engineering Genetic Transcription Genomic DNA Goals Histone Acetylation Immunotherapy Impairment Incidence Knowledge Lead Learning Los Angeles Malignant Neoplasms Mentors Mentorship Methodology Methylation Monitor Oncology Ontology Patients Pediatric Hematology Peripheral Phenotype Positioning Attribute Promoter Regions Recurrent disease Relapse Research Research Personnel Sampling Structure T cell therapy T-Cell Receptor T-Lymphocyte Therapeutic Time Training Transgenes Transgenic Organisms Transposase Treatment Failure Tumor Antigens Universities Work anti-cancer bisulfite sequencing cancer immunotherapy cancer therapy cancer type career cell age clinical decision-making cohort cytokine design epigenetic silencing epigenomic profiling epigenomics experience functional loss genetic element genetically modified cells in silico in vivo instructor loss of function novel patient response pediatric department promoter responders and non-responders response retroviral transduction skills transcriptome sequencing transcriptomics transgene expression translational study treatment response whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Cancer immunotherapy with T-cells expressing a transgenic T-cell receptor (TCR) can generate sustained clinical responses in a variety of malignancies. However, many patients do not respond, or eventually relapse. The goals of this proposal are to classify how progressive epigenomic and transcriptomic changes experienced by clinical transgenic TCR T-cells over time are associated with a gradual loss of function of these therapies, and how these changes correlate with clinical response or non-response to therapy. The proposed research focuses on the comparison of the epigenomic, transcriptomic, phenotypic, and functional characteristics of baseline transgenic TCR T-cells with samples recovered at later timepoints, utilizing a large cohort of clinical samples from patients treated with these cell therapeutics. In doing so, the candidate will address three main research aims: 1) Relate the epigenomic/transcriptomic changes experienced by transgenic T-cells over time, and their T-cell-specific in silico ontological/functional associations, with clinical response to therapy; 2) Define the transgenic T-cells’ progressive changes in phenotypic and cytokine secretion functionality profiles associated with clinical response or non-response to therapy; and 3) Determine the impact of epigenetic silencing on suppression of the expression of the transgenic TCR itself over time. The practical implications of this work include the enabling of highly detailed epigenomic profiling of a given patient’s transgenic T-cell therapeutics to help guide clinical decision-making, as well as provide novel targets for genetic engineering of newer generations of transgenic cellular therapies. The candidate is firmly committed to a career in translational cellular immunotherapy research, and is strongly supported in his career and research goals by his mentors and his department/division at the University of California, Los Angeles. He currently holds a position as a Clinical Instructor in the Department of Pediatrics, Division of Pediatric Hematology/Oncology, with 80% protected time for research. The current proposal builds on the candidate’s previous research and clinical experience by including a comprehensive mentorship and didactic plan to advance the candidate’s skills and knowledge in epigenomics and computational biology required for developing expertise in this area of focus. Under the guidance of his primary mentor, Dr. Antoni Ribas, and his Scientific Advisory Committee members Dr. Theodore Moore, Dr. Matteo Pellegrini, and Dr. Yvonne Chen, he will advance his bioinformatics skills, while learning epigenomic, T-cell phenotype profiling, and cytokinetic functionality methodologies that will be directly applied to this proposal. Completion of this comprehensive training and research plan will provide the candidate with the skills and experience necessary to become a successful independent investigator specializing in cellular immunotherapies for the treatment of cancer, with a focus on the cells’ epigenomic changes over time and their correlates with clinical response to therapy.

项目总结/摘要使用表达转基因T细胞受体（TCR）的T细胞的癌症免疫疗法可以产生持续的免疫应答。各种恶性肿瘤的临床反应。然而，许多患者没有反应，或最终复发。该提案的目标是对渐进的表观基因组学和转录组学变化进行分类，临床转基因TCRT细胞随着时间的推移与这些疗法的功能逐渐丧失有关，以及这些变化如何与治疗的临床反应或无反应相关。拟议的研究重点是比较表观基因组学，转录组学，表型和功能基线转基因TCR T细胞的特征与在稍后时间点回收的样品，利用大的来自用这些细胞治疗剂治疗的患者的临床样品的群组。在这样做时，候选人将解决三个主要的研究目标：1）涉及转基因动物经历的表观基因组/转录组变化， T细胞随时间的变化，以及它们的T细胞特异性计算机本体/功能关联，与对 2）定义转基因T细胞在表型和细胞因子分泌功能方面的进行性变化与治疗的临床反应或无反应相关的特征;和3）确定表观遗传学的影响，沉默对转基因TCR自身的表达随时间的抑制的影响。的实际影响这项工作包括对特定患者的转基因T细胞进行非常详细的表观基因组分析治疗，以帮助指导临床决策，以及为基因工程提供新的目标，新一代的转基因细胞疗法。候选人坚定地致力于转化细胞免疫治疗研究的职业生涯，并强烈在他的职业生涯和研究目标的支持下，他的导师和他的部门/部门在大学加州，洛杉矶。他目前担任儿科临床讲师，儿科血液学/肿瘤学分部，80%的研究时间受到保护。目前的建议是建立候选人以前的研究和临床经验，包括全面的指导，教学计划，以提高候选人的技能和知识，在表观基因组学和计算生物学所需的在这一重点领域发展专业知识。在他的主要导师Antoni Ribas博士的指导下，他的科学顾问委员会成员西奥多摩尔博士、马特奥·佩莱格里尼博士和陈伊冯博士，他将提高他的生物信息学技能，同时学习表观基因组学，T细胞表型分析和细胞动力学将直接应用于本提案的功能方法。完成这一全面培训和研究计划将为候选人提供必要的技能和经验，成为一个成功的独立研究者，专门从事细胞免疫疗法治疗癌症，重点关注细胞随时间的表观基因组变化及其与临床治疗反应的相关性。