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.

Public Health Relevance

The In Vivo Murine Models Core will provide essential technical and scientific expertise for in vivo modeling used in Projects focused on the development of novel cellular therapies ultimately intended for use in human subjects. Using humanized murine models tailored to meet experimental objectives, Core D will assist investigators by providing extensive preclinical in vivo data focused on establishing safety, cell distribution, efficacy, rationale for cell dosing, and mode of cell delivery. In addition, this Core will provide access to unique technologies, including novel imaging and cellular reprogramming. Additionally, this Core harmonizes its efforts with other Cores (Core A: Administrative and Translational Research Support Core, Core B: Biostatistics Core, and Core C: Translational Cell Therapy Core).

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Minnesota Twin Cities
United States
Zip Code
Owen, David L; Mahmud, Shawn A; Vang, Kieng B et al. (2018) Identification of Cellular Sources of IL-2 Needed for Regulatory T Cell Development and Homeostasis. J Immunol 200:3926-3933
Osborn, Mark J; Lees, Christopher J; McElroy, Amber N et al. (2018) CRISPR/Cas9-Based Cellular Engineering for Targeted Gene Overexpression. Int J Mol Sci 19:
Oh, Felix; Todhunter, Deborah; Taras, Elizabeth et al. (2018) Targeting EGFR and uPAR on human rhabdomyosarcoma, osteosarcoma, and ovarian adenocarcinoma with a bispecific ligand-directed toxin. Clin Pharmacol 10:113-121
Rashidi, Armin; Ebadi, Maryam; Said, Bassil et al. (2018) Absence of early HHV-6 reactivation after cord blood allograft predicts powerful graft-versus-tumor effect. Am J Hematol :
Bejanyan, Nelli; Brunstein, Claudio G; Cao, Qing et al. (2018) Delayed immune reconstitution after allogeneic transplantation increases the risks of mortality and chronic GVHD. Blood Adv 2:909-922
Bachanova, Veronika; Sarhan, Dhifaf; DeFor, Todd E et al. (2018) Haploidentical natural killer cells induce remissions in non-Hodgkin lymphoma patients with low levels of immune-suppressor cells. Cancer Immunol Immunother 67:483-494
Xing, Yan; Smith, Michelle J; Goetz, Christine A et al. (2018) Thymic Epithelial Cell Support of Thymopoiesis Does Not Require Klotho. J Immunol 201:3320-3328
Prestipino, Alessandro; Emhardt, Alica J; Aumann, Konrad et al. (2018) Oncogenic JAK2V617F causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms. Sci Transl Med 10:
de Witte, Moniek A; Sarhan, Dhifaf; Davis, Zachary et al. (2018) Early Reconstitution of NK and ?? T Cells and Its Implication for the Design of Post-Transplant Immunotherapy. Biol Blood Marrow Transplant 24:1152-1162
Zeiser, Robert; Blazar, Bruce R (2018) Acute Graft-versus-Host Disease. N Engl J Med 378:586

Showing the most recent 10 out of 395 publications