In the current funding we found that although NK cells reconstitute in high numbers early after allogeneic transplant, they display diminished killer immunoglobulin receptors (KIR), they are hypo-responsive and poorly kill tumor targets. Using in vitro development models, we also found that the acquisition of KIR and full effector function can be induced by IL-15. The overarching hypothesis of this Project is that NK cells early after hematopoetic transplantation are uneducated and that NK cell education is developmentally regulated by IL-15, activating receptors (2B4 Tim-3), and inhibitory receptor (KIR, NKG2A, LIR-1) ligation, all of which play a role in determining whether AML targets are killed. Promising results from Project 1 ofthe current funding show that allogeneic hematopoietic cell transplantation with favorable KIR B haplotype donors (enhanced by a higher B content score and a Cen-B/B pattern) results in protection from AML relapse. In a second strategy (Project 3), a platform for NK cell adoptive transfer has been established. To improve on existing methods, the NCI has recently developed a cGMP process for production of rhlL-15 which will be made available to the Extramural community. SAI will test IL-15 as part of a novel strategy to expand adoptively transferred adult NK cells. A second course of IL-15 will be given on Day +42 to educate NK cells that reconstitute from CD34+ stem cells from the same donor. In SA2, we will investigate whether KIR immunogenetics determines NK cell function (the favorable Cen-B/B pattern found clinically) and whether IL-15 responsive KIR promoter elements control transcriptional regulation to form the KIR repertoire. SA3 will evaluate a novel activating receptor expressed on most NK cells, Tim-3, which is upregulated by IL-15. We hypothesize it plays a role in NK cell education by upregulating the SAP adaptor (also IL-15 responsive) for 2B4. Tim-3 and 2B4 can directly recognize Galecfin-9 (Gal-9) and CD48 expressing AML targets or may indirectly receive activating signals from dendritic cells that express the same ligands. At completion of these studies, we expect to change practice of NK cell adoptive transfer by use of IL-15 and to inform us about IL-15 mechanisms to induce NK cell education and recognition of AML targets.

Public Health Relevance

Patients with advanced AML often die of their disease. We hypothesize that optimally activated NK cells will provide effective therapy for these patients. Our studies propose a first in human testing of rhlL-15 to activate and expand NK cells in vivo. Our preliminary data supports a central role for IL-15 to educate NK cells by upregulating receptor expression and function, which determine whether NK cells recognize AML targets.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA111412-09
Application #
8533760
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
9
Fiscal Year
2013
Total Cost
$259,578
Indirect Cost
$50,311
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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He, F; Warlick, E; Miller, J S et al. (2016) Lymphodepleting chemotherapy with donor lymphocyte infusion post-allogeneic HCT for hematological malignancies is associated with severe, but therapy-responsive aGvHD. Bone Marrow Transplant 51:1107-12
Weisdorf, Daniel (2016) The role of second transplants for leukemia. Best Pract Res Clin Haematol 29:359-364
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
Felices, Martin; Miller, Jeffrey S (2016) Targeting KIR Blockade in Multiple Myeloma: Trouble in Checkpoint Paradise? Clin Cancer Res 22:5161-5163
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Holtan, Shernan G; DeFor, Todd E; Lazaryan, Aleksandr et al. (2015) Composite end point of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation. Blood 125:1333-8
Schlums, Heinrich; Cichocki, Frank; Tesi, Bianca et al. (2015) Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function. Immunity 42:443-56

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