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 #
5P01CA111412-08
Application #
8321405
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
2012-08-01
Budget End
2013-07-31
Support Year
8
Fiscal Year
2012
Total Cost
$1,937,144
Indirect Cost
$376,500
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
Grzywacz, Bartosz; Moench, Laura; McKenna Jr, David et al. (2018) Natural Killer Cell Homing and Persistence in the Bone Marrow After Adoptive Immunotherapy Correlates With Better Leukemia Control. J Immunother :
Sarhan, Dhifaf; Hippen, Keli L; Lemire, Amanda et al. (2018) Adaptive NK Cells Resist Regulatory T-cell Suppression Driven by IL37. Cancer Immunol Res 6:766-775
Williams, Robin L; Cooley, Sarah; Bachanova, Veronika et al. (2018) Recipient T Cell Exhaustion and Successful Adoptive Transfer of Haploidentical Natural Killer Cells. Biol Blood Marrow Transplant 24:618-622
Don Yun, Hyun; Felices, Martin; Vallera, Daniel A et al. (2018) Trispecific killer engager CD16xIL15xCD33 potently induces NK cell activation and cytotoxicity against neoplastic mast cells. Blood Adv 2:1580-1584
Cooley, Sarah; Parham, Peter; Miller, Jeffrey S (2018) Strategies to activate NK cells to prevent relapse and induce remission following hematopoietic stem cell transplantation. Blood 131:1053-1062
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
Romee, Rizwan; Cooley, Sarah; Berrien-Elliott, Melissa M et al. (2018) First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation. Blood 131:2515-2527
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 :
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

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