In the previous funding period we identified immunogenetic loci that an unrelated donor (URD) KIR B haplotype yields statistically significant and meaningful improvement in protection against relapse and relapse free-survival fpr patients with AML. New analyses have refined the favprable KIR B loci to those which encode donor KIR activating receptors associated with improved clinical outcome. We will further explore the clinical importance of these genetic loci by prospectively evaluating the logistics and clinical impact of donor selection by KIR genotyping for URD hematopoietic cell transplantation (HCT) in AML. We hypothesize that amongst URD with optimal HLA matching, donor KIR genotyping can identify better donors likely to yield improved clinical outcome. In conjunction Project 1, we will explore the functional significance of these KIR B loci, their interaction with HLA Class I and allelic polymorphism in the KIR regions to further refine our understanding and methods for prospective donor selection. With Project 2 we will analyze NK cell functional development over time after URD HCT and correlation of this NK development with the complications following HCT including engraftment, GVHD, infections, relapse and survival. These unique analyses accompany a BMT CTN prospective trial testing blood vs. marrow as a graft source for URD HCT and offer a unique platform for understanding how NK cell development, KIR genotyping and functional immune reconstitution can modify post-transplant complications and outcomes. Additionally, the fundamentals of NK cell therapy to reduce recurrence of resistant leukemia and improve sun/ival after transplantation will.be directly tested. In a multicenter trial of reduced intensity haploidentical HCT plus donor NK infusions for resistant AML we will evaluate the direct impact of NK cell therapy on highly resistant leukemia. Prospective clinical trials will define elements essential for safer application of this treatment. Overall, these studies can improve the survival and relapse protection following allogeneic HCT for AML. Our studies outline new and exciting opportunities to improve donor selection and maximize the safety and effectiveness of allotransplantation.

Public Health Relevance

Patients with advanced acute leukemia can be treated with donor transplantation, but improved means to select donors, enhance immune recovery after transplantation and control the risks of relapse have direct application in improving patient survival. These studies will change transplant practice to utilize NK cells to make transplantation safer and more effective.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA111412-09
Application #
8533762
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
$461,157
Indirect Cost
$50,312
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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

Showing the most recent 10 out of 74 publications