The theme of this program has not changed over the last decade: Understanding the biology of human hematopoietic stem cells (HSC) and their progeny will lead to improved hematopoietic cell-based therapy for a variety of lethal malignant diseases. During the current funding period, Catherine Verfaillie MD has made important observations on mechanisms governing stem cell self-renewal and differentiation. Recently, she has developed a high through-put zebrafish screen to characterize a variety of genes differentially expressed in Rho'x and Rho hi human umbilical cord blood (UCB) progenitors which may affect self-renewal of hematopoietic stem cells. In Project 1, she will exploit the high through-put zebrafish screening assay to assess the potential role of these genes in hematopoiesis, and confirm such a role in subsequent in vitro progenitor assays and murine transplant models. She will employ a similar approach to characterize genes differentially expressed in stromal feeders that support or do not support HSC in non-contact cultures. This approach may identify novel extrinsic factors that regulate HSC self-renewal. Genes and their products implicated by Dr. Verfaillie in hematopoietic stem cell self-renewal will be assessed in preclinical and clinical studies in Project 2 for their capacity to enhance engraftment in UCB transplant trials and in Project 3 to determine their effect on myeloid and lymphoid progenitor differentiation. During the current funding period, John Wagner MD has developed a """"""""double UCB"""""""" transplant approach which has significantly broadened the availability of UCB transplants to treat adults, regardless of body size. The double UCBT model also allows manipulation and tracking of cells from one transplanted UCB unit while providing a second, unmanipulated unit to safeguard engraftment. In Project 2, Dr. Wagner will use the double UCBT model to test novel methods to enhance engraftment by co-infusion of regulatory T-cells (Treg), and use of novel ex vivo expansion approaches evolving from Project 1. He will also use immunocompromised mouse transplant models to explore immunological events underlying double UCB transplants. Jeffrey Miller MD has made the startling observation that infusion of HLA haploidentical NK cells in the non-transplant setting is associated with complete remission in some patients with high-risk AML. Clinical responses are correlated with in vivo donor NK expansion. In Project 3, he will continue a series of clinical trials testing NK cell-based cell therapy for leukemia. He will also continue to examine fundamental events shaping NK cell progenitor differentiation, activation and proliferation, and assess the influence of novel ex vivo HSC expansion conditions developed in Projects 1 on myeloid and lymphoid differentiation. These interactive projects are supported by administrative and biostatistical cores (Cores A and B), as well as cores to provide cell collection and processing (Core C) and immunocompromised mouse assays (Core D).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA065493-12
Application #
7114966
Study Section
Special Emphasis Panel (ZCA1-GRB-J (M1))
Program Officer
Merritt, William D
Project Start
1997-09-15
Project End
2010-06-30
Budget Start
2006-09-28
Budget End
2007-06-30
Support Year
12
Fiscal Year
2006
Total Cost
$2,072,348
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Williams, Shelly M; Sumstad, Darin; Kadidlo, Diane et al. (2018) Clinical-scale production of cGMP compliant CD3/CD19 cell-depleted NK cells in the evolution of NK cell immunotherapy at a single institution. Transfusion 58:1458-1467

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