Transplant donors have either the B/x or A/A KIR genotype. During the current period of support we found that unrelated donors having B/x genotype confer significant relapse-free survival benefit to transplanted AML patients. By refining the analysis to separate B haplotype components, we defined a 'B-content score'as the best predictor of superior clinical outcomes. We propose that donor selection based on KIR, as well as HLA, genotyping should become standard practice for therapeutic transplants for AML. This Program will test the hypotheses that NK cells are of general importance in allogeneic transplantation and that variable NK cell receptor interactions influence clinical outcome. Conducting this Program is an international group of experts in NK cell biology and clinical transplantation. A focus for study is the thousands of transplants performed through the auspices of the NMDP, their associated blood and DNA samples, and the extensive high quality data on transplant outcome available through the CIBMTR. Project 1 (Peter Parham) will focus on the functions of characteristic B haplotype KIR, to determine the mechanisms by which they can influence transplant outcome. In Project 2, Jeffrey Miller proposes to evaluate NK cell education after adoptive transfer of haploidentical stem cells and subsequent reconstitution. He proposes a first human trial to investigate the capacity of hulL-15 to educate NK cells in vivo. In Project 3, Daniel Weisdorf will develop KIR typing for clinical use in selecting donors with KIR that improve transplant outcome. This method will also be used in the human trial of Project 2. Synergistic interaction between the Projects will take basic NK cell science from bench to bedside. Achieving this goal through better donor selection, understanding of NK cell regulation by KIR genetics and how best to exploit this knowledge clinically. As well as Administration and Clinical Research Support (Core A) and Biostatistics (Core B), the research will be supported by unique Informatics (Core C) and KIR genotyping (Core D) resources. This program will establish definitive roles for NK cells and their receptors in allogeneic transplantation and adoptive NK cell transfer. The program also promises to change practice of allogeneic transplantation, to the greater benefit of patients with advanced leukemia.

Public Health Relevance

Patients with advanced leukemia will die of their disease unless they receive hematopoetic cell transplantation, and two thirds will require transplantation from unrelated donors. This program will improve transplant outcome by taking account of NK cell receptor genes to select donors that will reduce relapse of leukemia and increase survival ofthe transplant recipient

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA111412-10
Application #
8721712
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (M1))
Program Officer
Merritt, William D
Project Start
2004-12-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
10
Fiscal Year
2014
Total Cost
$1,866,115
Indirect Cost
$361,686
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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Cichocki, Frank; Schlums, Heinrich; Li, Hongchuan et al. (2014) Transcriptional regulation of Munc13-4 expression in cytotoxic lymphocytes is disrupted by an intronic mutation associated with a primary immunodeficiency. J Exp Med 211:1079-91
Cooley, Sarah; Weisdorf, Daniel J; Guethlein, Lisbeth A et al. (2014) Donor killer cell Ig-like receptor B haplotypes, recipient HLA-C1, and HLA-C mismatch enhance the clinical benefit of unrelated transplantation for acute myelogenous leukemia. J Immunol 192:4592-600
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Foley, Bree; Felices, Martin; Cichocki, Frank et al. (2014) The biology of NK cells and their receptors affects clinical outcomes after hematopoietic cell transplantation (HCT). Immunol Rev 258:45-63
Miller, Jeffrey S; Rooney, Cliona M; Curtsinger, Julie et al. (2014) Expansion and homing of adoptively transferred human natural killer cells in immunodeficient mice varies with product preparation and in vivo cytokine administration: implications for clinical therapy. Biol Blood Marrow Transplant 20:1252-7
Felices, Martin; Lenvik, Todd R; Ankarlo, Dave E M et al. (2014) Functional NK cell repertoires are maintained through IL-2R? and Fas ligand. J Immunol 192:3889-97
Gleason, Michelle K; Ross, Julie A; Warlick, Erica D et al. (2014) CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets. Blood 123:3016-26
Sarkar, Chandrima; Cooley, Sarah; Srivastava, Jaideep (2014) Robust Feature Selection Technique using Rank Aggregation. Appl Artif Intell 28:243-257
Bachanova, Veronika; Cooley, Sarah; Defor, Todd E et al. (2014) Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein. Blood 123:3855-63

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