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

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-J (M1))
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Merritt, William D
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University of Minnesota Twin Cities
Internal Medicine/Medicine
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Cichocki, Frank; Verneris, Michael R; Cooley, Sarah et al. (2016) The Past, Present, and Future of NK Cells in Hematopoietic Cell Transplantation and Adoptive Transfer. Curr Top Microbiol Immunol 395:225-43
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
Schmohl, Joerg U; Felices, Martin; Taras, Elizabeth et al. (2016) Enhanced ADCC and NK Cell Activation of an Anticarcinoma Bispecific Antibody by Genetic Insertion of a Modified IL-15 Cross-linker. Mol Ther 24:1312-22
Horowitz, Amir; Guethlein, Lisbeth A; Nemat-Gorgani, Neda et al. (2015) Regulation of Adaptive NK Cells and CD8 T Cells by HLA-C Correlates with Allogeneic Hematopoietic Cell Transplantation and with Cytomegalovirus Reactivation. J Immunol 195:4524-36
Holtan, Shernan G; Verneris, Michael R; Schultz, Kirk R et al. (2015) Circulating angiogenic factors associated with response and survival in patients with acute graft-versus-host disease: results from Blood and Marrow Transplant Clinical Trials Network 0302 and 0802. Biol Blood Marrow Transplant 21:1029-36
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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