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Principal Investigator: Theodore Lee Roth
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $330,942
Funding agency: National Cancer Institute
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.
Terms: <Advisory Committees><Antigen Receptors><Assay><Autoimmune><Behavior><Bioassay><Biological Assay><CAR T cell therapy><CAR T cells><CAR T therapy><CAR modified T cells><CAR-T><CAR-Ts><Cancer Patient><Cancers><Career Development Awards><Career Development Awards and Programs><Career Development Programs K-Series><Cell Body><Cell Compartmentation><Cell Compartmentations><Cell Function><Cell Physiology><Cell Process><Cell Therapy><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular immunotherapy><Clinical><Clinical Trials><Communities><Complement><Complement Proteins><Data><Data Set><Diagnostic tests><Doctor of Philosophy><Engineering><Ensure><Environment><FDA approved><Ferroprotoporphyrin><Foundations><Funding><Future><Gene Targeting><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genotype><Goals><Heme><Immune><Immune mediated therapy><Immune system><Immunes><Immunologically Directed Therapy><Immunotherapy><In Vitro><K-Awards><K-Series Research Career Programs><Knock-in><Libraries><Liquid substance><Malignant Neoplasms><Malignant Tumor><Measurement><Mentors><Metadata><Methodology><Modeling><Modification><Molecular><Mutation><Nature><Oncology><Oncology Cancer><Pathologist><Pathology><Patients><Performance><Ph.D.><PhD><Phase><Phenotype><Physicians><Protoheme><Publishing><Relapse><Research><Research Career Program><Residencies><Running><Scientist><Solid Neoplasm><Solid Tumor><Subcellular Process><Surface><System><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell targeted therapeutics><T cell therapy><T cells for CAR><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><Task Forces><Technology><Testing><Therapeutic><Training><Tumor Cell Line><Universities><Work><Xenograft Model><adoptive T cell transfer><adoptive T-cell therapy><advisory team><anti-cancer immunotherapy><anticancer immunotherapy><assay development><cancer immunotherapy><career><career development><cell engineering><cell mediated therapies><cell-based immunotherapy><cell-based therapeutic><cell-based therapy><cellular engineering><cellular therapeutic><cellular therapy><check point blockade><checkpoint blockade><chimeric antigen T cell receptor><chimeric antigen receptor><chimeric antigen receptor (CAR) T cell therapy><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cell therapy><chimeric antigen receptor T cells><chimeric antigen receptor T therapy><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><cohort><complementation><cost><diagnostic approach><diagnostic assay><diagnostic strategy><effective therapy><effective treatment><engineered T cells><engineered immune system><ferroheme><fluid><genetically engineered T-cells><genome mutation><high dimensionality><immune cell therapy><immune check point blockade><immune checkpoint blockade><immune engineering><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunoengineering><immunotherapy for cancer><immunotherapy of cancer><in vivo><individual patient><individualized strategies><knockin><leukemia/lymphoma><liquid><lymphoma/leukemia><malignancy><meta data><multidisciplinary><neoplasm/cancer><patient response><patient specific response><patient variability><patient variation><personalized strategies><pre-clinical><preclinical><programs><rapid assay><rapid test><rapid tests><resistance mechanism><resistant mechanism><responsive patient><screening><screenings><side effect><success><therapeutic T-cell platform><thymus derived lymphocyte><transgenic T- cells><tumor><variability between patients><variation between patients><xenograft transplant model><xenotransplant model>