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

项目摘要/摘要 NCI职业发展奖的候选人是Max Jan，医学博士，已完成临床培训 目前是马萨诸塞州综合医院的博士后研究员 (MGH)。简博士加入了本杰明·埃伯特的实验室，他是血液学研究的全球领先者 恶性肿瘤和靶向蛋白质降解作为癌症的治疗概念。简博士的联合导师是 Marcela Maus，细胞免疫治疗领域的全球领先者。中国经济的近期目标 候选人将完成他提出的科学目标，这些目标围绕着重新编程表观基因组 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 解决免疫细胞疗法治疗癌症的一个根本局限性，即癌症往往能够逃脱 通过诱导免疫细胞失调和抑制来进行这种治疗。应聘者将开发方法来 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(目标1)。化学生物学 然后，将使用一种方法在基线和重新编程的表观遗传状态之间切换，以便研究 管理这一进程的直接和直接机制(目标2)。最后，受监管、可切换的影响 将测试长期CAR T细胞效应器功能的表观基因组重编程(目标3)。完成 这些目标将在智力和技术上为简博士向独立过渡做好准备。候选人的短片- 和长期目标直接关系到NCI的使命，并追求科学知识，以便 使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疗法的反应，以设计出更安全、更 实体和血癌患者的有效细胞免疫疗法。这位候选人已经领先一位。 有指导的职业发展计划，重点是单细胞基因组学和表观遗传学方面的技术培训，如 以及学术和领导能力。候选人在以下方面获得杰出的机构和部门支持 在MGH，他可以充分利用优秀的技术和智力资源。应聘者收到 来自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 内科医生兼科学家成为独立调查人员。最后，候选人开发了一种科学的 由癌症相关领域备受尊敬的医生和研究人员组成的咨询委员会 免疫学和基因组学将提供经验丰富和可靠的指导。这份职业发展 获奖将大大促进Max Jan向独立的过渡，成为一名致力于研究 免疫疗法，以改善癌症患者的生活。

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.