Dissecting intrinsic variability in engineered T Cell immunotherapies

PROJECT SUMMARY/ABSTRACT Cancer immunotherapy has revolutionized oncology. Chimeric Antigen Receptor (CAR) T cells in particular have shown dramatic successes in some liquid tumors, with multiple FDA approved products in overlapping heme indications. Yet patient responses to engineered cell therapies are highly variable and unpredictable. Given both

the extraordinary cost and extraordinary curative potential of engineered T cell therapies, matching the right cell to the right patient remains a large unmet clinical need. Yet how patient T cells variably respond to the wealth of different potential synthetic genetic alterations remains unexplored. Our long term goal is to develop personalized

cellular immunotherapies and the diagnostic tests necessary to nominate the optimal engineered cell for a specific cancer patient. As a first step towards this goal, we will develop scalable pooled screening methodologies to rapidly assay approved and proposed cellular immunotherapy constructs at scale across large

numbers of patients (Specific Aim 1). In cohorts of liquid and solid tumor patients, we will dissect the intrinsic variability of patient T cells synthetically engineered with CARs in repetitive stimulation assay models (Specific Aim 2). Finally, we will determine predictive correlates of patient specific engineered T cell function using high

dimensional immune cell profiling and patient clinical metadata (Specific Aim 3). We hypothesize that engineered immune cell performance is highly variable and patient specific, and measurements of this variability across cancer patient’s T cells will nominate future predictive diagnostic strategies for personalized cellular

immunotherapy choice. In this K08 Mentored Clinical Scientist Research Career Development Award application, the applicant, Dr. Theodore Roth, MD, PhD is a Clinical Pathologist in the Stanford University Department of Pathology. In addition to the enclosed Research Plan, this proposal encompasses a five-year Training Plan to

complete his mentored career development with the primary goal of becoming and independent academic physician scientist running a research group devoted to developing personalized cellular immunotherapies. Dr. Roth will undergo training in diagnostic assay development (Training Aim 1), high dimensional immune profiling

technologies (Training Aim 2), and successful assumption of research independence (Training Aim 3). Dr. Roth’s remaining mentored training will be overseen by a multidisciplinary group of distinguished physician scientists, including his primary mentor Dr. Ansuman Satpathy and co-mentor Dr. Crystal Mackall, along with a senior

Advisory Committee composed of Drs. Ed Engleman, Howard Chang, and David Miklos. Stanford University provides an outstanding environment to complete Dr. Roth’s transition to research independence, with a highly active clinical cell therapy program overseen by his co-mentor, Dr. Crystal Mackall, and vibrant research

communities in immunotherapy, genetics, diagnostic assay development, and high dimensional molecular technologies. Completion of the Research and Training Plans will propel Dr. Roth’s independent research career as an academic physician scientist.