During the current funding period we demonstrated the significant anti-leukemic potential of adoptively transferred adult NK cells by effecting complete remissions in patients with advanced AML. This project will include novel clinical trials designed to improve techniques exploiting NK cell alloreactivity in umbilical cord blood (UCB) transplants as well as in vitro and murine experiments to characterize the mechanisms supporting the expansion and education of NK cells derived from adult blood and from UCB progenitors. In SA1, we will perform a series of clinical trials assessing the efficacy of IL-2 administration to enhance in vivo NK cell expansion and education in an adult NK cell adoptive transfer/T cell depleted UCB transplantation strategy. We have generated in vitro data suggesting an important effect of IL-15 on NK cell expansion and differentiation. Clinical grade IL-15 has recently been made available to us by the NCI, and we will next substitute IL-15 for IL-2 in the first human trial to test the ability of IL-15 to facilitate education of engrafting NK cells after UCB transplant. A third clinical trial will test the hypothesis that adoptive transfer of >10 fold higher doses of ex vivo expanded adult NK cells will further enhance efficacy. In SA2 we will monitor the receptor repertoires, function and education of NK cells expanding in patients exposed to IL-2 or IL-15, after Treg infusion from the UCB transplant trials in Project 1 (Wagner), and in transplant recipients responding to viral stress. We will also use pre-clincial in vitro assays and a murine model in which adult human NK cells and UCB progenitors are transferred into NOD SCID IL2Rgamma-c-null immunodeficient mice to test novel strategies to enhance NK cell function. Specifically, we will test methods to enhance the anti-leukemic function of NK cells with potential for translation into clinical trials. We will test trans-presentation of IL-15 using lL-15Ra-Fc, ex vivo NK cell expansion using IL-15Ra+ artificial K562 cell stimulator cells (? Notch ligand or41BB ligand), and techniques to tailor the allo-reactive specificity of ex vivo expanded NK cells by culture with K562 stimulators expressing single Bw4, C1 or C2 KIR ligands. Ultimately, the best strategy from this series of clinical trials designed to optimize the anti-leukemic effect of NK cells will be combined with the clinical methods to enhance immune reconstitution and minimize GVHD developed in Project 1 and in Project 2.

Public Health Relevance

Patients with advanced AML often die of their disease and have no curative treatment options. We hypothesize that the persistence, expansion and function of NK cells after adoptive transfer will correlate with efficacy. Optimizing NK cell therapy with umbilical cord transplant has the potential to offer new therapies to patients and change transplant platforms to improve treatment outcomes for cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
3P01CA065493-18S1
Application #
8533736
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
1997-09-15
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
18
Fiscal Year
2012
Total Cost
$9,296
Indirect Cost
$3,180
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Turcotte, Lucie M; Yingst, Ashley; Verneris, Michael R (2016) Metabolic Syndrome after Hematopoietic Cell Transplantation: At the Intersection of Treatment Toxicity and Immune Dysfunction. Biol Blood Marrow Transplant 22:1159-66
Eckfeldt, Craig E; Randall, Nicole; Shanley, Ryan M et al. (2016) Umbilical cord blood transplantation is a suitable option for consolidation of acute myeloid leukemia with FLT3-ITD. Haematologica 101:e348-51
Sarhan, Dhifaf; Cichocki, Frank; Zhang, Bin et al. (2016) Adaptive NK Cells with Low TIGIT Expression Are Inherently Resistant to Myeloid-Derived Suppressor Cells. Cancer Res 76:5696-5706
Pritchett, Joshua C; Green, Jaime S; Thomm, Angela M et al. (2016) CD4+ T Cells Coexpressing CD134 (OX40) Harbor Significantly Increased Levels of Human Herpesvirus 6B DNA Following Umbilical Cord Blood Transplantation. J Infect Dis 214:1911-1915
Trottier, B J; Sachs, Z; DeFor, T E et al. (2016) Novel disease burden assessment predicts allogeneic transplantation outcomes in myelodysplastic syndrome. Bone Marrow Transplant 51:199-204
Brinkman, C Colin; Iwami, Daiki; Hritzo, Molly K et al. (2016) Treg engage lymphotoxin beta receptor for afferent lymphatic transendothelial migration. Nat Commun 7:12021
Brunstein, Claudio G; Miller, Jeffrey S; McKenna, David H et al. (2016) Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect. Blood 127:1044-51
Nakamura, Ryotaro; La Rosa, Corinna; Longmate, Jeffrey et al. (2016) Viraemia, immunogenicity, and survival outcomes of cytomegalovirus chimeric epitope vaccine supplemented with PF03512676 (CMVPepVax) in allogeneic haemopoietic stem-cell transplantation: randomised phase 1b trial. Lancet Haematol 3:e87-98
Omer, Aazim K; Weisdorf, Daniel J; Lazaryan, Aleksandr et al. (2016) Late Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 22:879-83
Knorr, David A; Wang, Hongbo; Aurora, Mukta et al. (2016) Loss of T Follicular Helper Cells in the Peripheral Blood of Patients with Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant 22:825-33

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