Reprogramming the chimeric antigen receptor T cell epigenome to augment anti-tumor activity

重编程嵌合抗原受体 T 细胞表观基因组以增强抗肿瘤活性

• 批准号: 10579259
• 负责人: Max Jan
• 金额: $ 18.94万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579259
• 关键词: Achyrocline; Advisory Committees; Area; Biology; Cell Therapy; Cell physiology; Cells; Cellular immunotherapy; Chemicals; Chromatin Modeling; Clinical; DNA Methylation; DNMT3a; DNMT3a mutation; Data; Dedications; Defect; Development Plans; Doctor of Philosophy; Dominant-Negative Mutation; Effectiveness; Engineering; Epigenetic Process; Functional disorder; Gene Expression Profiling; General Hospitals; Genes; Genomics; Glues; Goals; Growth; Hematologic Neoplasms; Hematopoietic Neoplasms; Immune; Immunotherapy; Impairment; In Vitro; Institution; K-Series Research Career Programs; Knowledge; Laboratories; Leadership; Malignant Neoplasms; Maps; Massachusetts; Mediating; Memory; Mentors; Mentorship; Methods; Mission; Molecular; Molecular Genetics; Mutate; Outcome; Pathology; Patients; Persons; Pharmaceutical Preparations; Physicians; Postdoctoral Fellow; Process; Proteins; Records; Regulator Genes; Research Personnel; Research Project Grants; Resources; Risk; Role; Route; Schedule; Scientist; Solid; Solid Neoplasm; System; T cell response; T cell therapy; T-Lymphocyte; Testing; Therapeutic; Training; Treatment Failure; Treatment outcome; Tumor Suppression; Tumor Suppressor Proteins; Variant; Work; cancer genomics; cancer therapy; cancer type; career development; chimeric antigen receptor; chimeric antigen receptor T cells; clinical training; combat; cost; design; drug action; effector T cell; epigenome; epigenomics; experience; genetic manipulation; improved; in vivo; interest; lenalidomide; loss of function; multicatalytic endopeptidase complex; mutant; next generation; novel strategies; overexpression; patient response; polypeptide; programs; protein degradation; self-renewal; single-cell RNA sequencing; skills; tool; tumor; tumor immunology; tumor microenvironment; ubiquitin-protein ligase

PROJECT SUMMARY/ABSTRACT The candidate for this NCI Career Development Award is Max Jan, MD, PhD, who has completed clinical training in molecular genetic pathology and is a current postdoctoral researcher at Massachusetts General Hospital (MGH). Dr. Jan has joined the laboratory of Benjamin Ebert, a worldwide leader in the study of hematologic malignancies and targeted protein degradation as a therapeutic concept in cancer. Dr. Jan is co-mentored by Marcela Maus, a worldwide leader in the field of cellular immunotherapy. An immediate-term goal for the candidate is to complete his proposed scientific Aims, which center around reprogramming the epigenome of chimeric antigen receptor (CAR) T cells in order to increase their anti-tumor activity. The proposed work will address a fundamental limitation of immune cell therapies for cancer, that cancers are too often able to evade such therapies by inducing immune cell dysregulation and suppression. The candidate will develop methods to reprogram the CAR T cell epigenome to enhance persistence and anti-tumor activity (Aim 1). A chemical biology approach will then be used to switch between baseline and reprogrammed epigenetic states, in order to study the immediate and direct mechanisms governing this process (Aim 2). Finally, the impact of regulated, switchable epigenomic reprogramming on long-term CAR T cell effector functions will be tested (Aim 3). The completion of these aims will intellectually and technically prepare Dr. Jan to transition to independence. The candidate’s short- and long-term goals are directly relevant to the mission of the NCI, and pursue scientific knowledge in order to more successfully treat patients with cancer using immune cell therapies. In the long term, the candidate will continue to study patient responses to immune therapy in order to engineer next generations of safer and more effective cellular immunotherapies for patients with solid and blood cancers. The candidate has advanced a mentored career development plan centered on technical training in single cell genomics and epigenetics, as well as academic and leadership skills. The candidate has outstanding institutional and departmental support at MGH, where he has full access to excellent technical and intellectual resources. The candidate receives enthusiastic support from his prior and current mentors, who have outstanding track records for training physician-scientist to become independent investigators. Finally, the candidate has developed a scientific advisory committee composed of highly regarded physician-investigators in the relevant areas of cancer immunology and genomics who will provide experienced and sure-handed mentorship. This career development award will greatly enhance Max Jan’s transition to independence as an investigator dedicated to the study of immune therapies to improve the lives of people with cancer.

项目总结/摘要 这个NCI职业发展奖的候选人是Max Jan，MD，PhD，他已经完成了临床培训 目前是马萨诸塞州总医院的博士后研究员 （MGH）. Jan博士加入了Benjamin Ebert的实验室，Benjamin Ebert是血液学研究的全球领导者。 恶性肿瘤和靶向蛋白质降解作为癌症的治疗概念。杨博士是共同辅导， Marcela Maus是细胞免疫治疗领域的全球领导者。一个短期目标， 候选人是为了完成他提出的科学目标，其中心是重新编程的表观基因组， 嵌合抗原受体（CAR）T细胞，以增加其抗肿瘤活性。拟议的工作将 解决了癌症免疫细胞疗法的根本局限性，癌症往往能够逃避 这些疗法通过诱导免疫细胞失调和抑制来实现。候选人将制定方法， 重新编程CAR T细胞表观基因组以增强持久性和抗肿瘤活性（Aim 1）。化学生物学 然后将使用这种方法在基线和重新编程的表观遗传状态之间切换，以研究 管理这一过程的直接机制（目标2）。最后，受监管的、可转换的 将测试表观基因组重编程对长期CAR T细胞效应子功能的影响（目的3）。完成 这些目标将在智力和技术上为简博士过渡到独立做好准备。候选人很矮- 长期目标与国家癌症研究所的使命直接相关，追求科学知识， 用免疫细胞疗法更成功地治疗癌症患者。从长远来看，候选人将 继续研究患者对免疫治疗的反应，以设计下一代更安全， 有效的细胞免疫疗法用于实体癌和血癌患者。候选人已经提出了一个 指导的职业发展计划集中在单细胞基因组学和表观遗传学的技术培训， 以及学术和领导能力。候选人在以下方面得到了出色的机构和部门支持： MGH，在那里他可以充分利用优秀的技术和智力资源。候选人收到 他的前任和现任导师的热情支持，他们在培训方面有着出色的记录 成为独立的研究者。最后，候选人已经制定了一个科学的 咨询委员会由癌症相关领域备受推崇的医生-研究人员组成 免疫学和基因组学谁将提供经验丰富和可靠的指导。这种职业发展 该奖项将大大提高马克斯扬的过渡到独立作为一个研究人员致力于研究 免疫疗法来改善癌症患者的生活。