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.
Cellular immunotherapies such as transgenic T-cell receptor (TCR) T-cells are revolutionizing the treatment of multiple cancer types, but there remain significant incidences of treatment failure or relapsed disease after an initial clinical response. I propose that the DNA accessibility of these transgenic T-cells changes over time, can ultimately impair the cells? anti-cancer functionality, and are associated with treatment failure. This research plan will examine samples of transgenic TCR T-cells from patients receiving them for cancer treatment, and compare the cells? DNA accessibility, gene expression patterns, and their associated functionality over time with the patients? response rates to their transgenic cell therapy, and identify factors which are associated with this phenomenon.