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

• 批准号: 10348735
• 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
• 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/10348735
• 关键词: ATAC-seq; Address; Advisory Committees; Area; Bioinformatics; Biological; Biological Assay; California; Cell Therapy; Cell physiology; Cells; Cellular immunotherapy; Characteristics; Chromatin; 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; base; bisulfite sequencing; cancer immunotherapy; cancer therapy; cancer type; career; cell age; clinical decision-making; cohort; cytokine; design; epigenetic silencing; epigenomics; experience; 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; translational study; treatment response; whole genome

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.

项目概要/摘要 使用表达转基因 T 细胞受体 (TCR) 的 T 细胞进行癌症免疫治疗可以产生持续的 多种恶性肿瘤的临床反应。然而，许多患者没有反应，或者最终复发。 该提案的目标是对表观基因组和转录组的进展变化进行分类 随着时间的推移，临床转基因 TCR T 细胞的作用与这些疗法的功能逐渐丧失相关， 以及这些变化如何与治疗的临床反应或无反应相关。 拟议的研究重点是表观基因组、转录组、表型和功能的比较 基线转基因 TCR T 细胞的特征以及在稍后时间点回收的样本，利用大量 来自接受这些细胞疗法治疗的患者的临床样本队列。在此过程中，候选人将 解决三个主要研究目标：1）将转基因经历的表观基因组/转录组变化联系起来 随着时间的推移，T 细胞及其在计算机本体/功能关联中的 T 细胞特异性，以及临床反应 治疗; 2) 定义转基因T细胞表型和细胞因子分泌功能的渐进变化 与治疗的临床反应或无反应相关的概况； 3) 确定表观遗传的影响 沉默对转基因TCR本身的表达随时间的抑制。的实际意义 这项工作包括对特定患者的转基因 T 细胞进行高度详细的表观基因组分析 治疗方法有助于指导临床决策，并为基因工程提供新的靶标 新一代转基因细胞疗法。 该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 他的导师和他在大学的系/部门支持他的职业和研究目标 加利福尼亚州、洛杉矶。他目前担任儿科临床讲师， 儿科血液学/肿瘤学部门，80% 的研究时间受到保护。目前的提案构建 候选人之前的研究和临床经验，包括全面的指导和 提高候选人在表观基因组学和计算生物学方面的技能和知识的教学计划 发展该重点领域的专业知识。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、马泰奥·佩莱格里尼博士和伊冯·陈博士， 他将提高他的生物信息学技能，同时学习表观基因组、T 细胞表型分析和细胞因子 将直接应用于该提案的功能方法。完成本次综合 培训和研究计划将为候选人提供成为成为一名 成功的独立研究者，专门从事癌症治疗的细胞免疫疗法，具有 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。