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

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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.