Abstract The foremost function of the In Vivo Murine Models Core is to provide safety and efficacy testing of human cell therapies in a murine model. This in vivo step is a critical precursor to human clinical trials. We will use our extensive experience to provide state-of-the-art murine experimental modeling that is tailored to the research objectives of the Projects and streamlines the Projects in several ways: (1) It provides centralized animal care for multiple breeding colonies and the stock of mice as needed by Projects 1, 2, and 3, as well as the validation studies in Core C (Aim 1). (2) By focusing the murine research into Core D, each of the Projects is equally supported by high-quality laboratory performance and inventive experimental approaches (Aim 2), intellectual partnership, and consistent reporting of data. (3) In a rapidly evolving field, it is an advantage to be able to apply knowledge learned from one Project to all the models as needed. The Specific Aims of this Core are as follows: Aim 1: Investigate the function, potency, and safety of manipulated human hematopoietic cell populations using state-of-the-art murine models in support of the experimental studies outlined in each of the Projects and Core C. Specifically, we plan to establish proof-of-concept and safety data for T progenitor (Tprog) cells (Project 1), drug-regulated chimeric antigen receptor (CAR)-modified T stem cell memory (Tsm) cells (Project 2), and adaptive Natural Killer (NK) cells (Project 3). Aim 2: Provide unique expertise and new technologies that will enhance functional assessments and analysis of cell distribution and survival. We will tailor animal models and methods of assessment to fit the needs of specific projects, ranging from the use of deuterium labeling of human Tprog cells (Project 1), to the evaluation of pluripotency from manufactured human Tsm-derived induced pluripotent stem cells (iPSC) (Project 2), to the assessment of constitutive and drug-regulated CAR+ T cells and adaptive NK cell-directed responses against primary leukemia targets (Projects 2 and 3). The ability to apply immune cells as special delivery agents?Treg to suppress graft-versus-host disease, Tprog to function as an ?immune bridge? during immune reconstitution, Tsm to improve longevity of CAR+ T cells and to serve as renewable cell therapy source, drug-regulated CAR+ T cells to minimize side effects of CAR-based therapies, and adaptive NK cells to prevent and treat leukemia relapse?will enable translation of these advanced immune reconstitution and anti-leukemia therapies to humans. Our ambition is to continue to meet experimental changes and challenges with the utmost versatility. Thus, Core D will work in synthesis with all three Projects to provide a support platform for them. This coordination will in turn inform the cell manufacturing and the design of future clinical trials.