Advanced cancer continues to be a major health problem in US and scientific advances suggest that manipulating the immune response may result in effective anti-tumor therapy. This Program is led by an international group of experts in NK cell biology and clinical transplantation. We have studied DNA from thousands of hematopoietic cell transplants facilitated by the National Marrow Donor Program, to correlate donor genetics with transplant outcome using outcome data from the CIBMTR. This is one of the only Program Project Grant focused solely on human NK cell biology and therapy. We have made great progress during the current funding and have made a number of scientific observations that drive the innovation of this revised renewal. We discovered that killer-immunoglobulin receptor (KIR) gene interactions with MHC class I molecules impact clinical outcomes, safely performed the first-in-human testing of IL-15 and IL-15/IL-15R?-Fc superagonist complexes, developed strategies to make NK cells specific for target antigens and discovered unique properties of CMV-induced adaptive NK cell in humans with memory like properties and altered function. Transplant donors and cancer patients can be defined by NK cell receptor genes of the KIR A or B haplotype. During the current period of support we found that unrelated donors with favorable KIR genes confer significant relapse-free survival benefit to transplanted AML patients containing at least copy of HLA-C1. Project 1 (Peter Parham) will focus on the functions of KIR B haplotype genes using novel functional assays to precisely interrogate interaction with MHC using mass cytometry. He will expand KIR analyses by high resolution sequenced typing in AML cohorts. This will yield an unprecedented high resolution of immune reconstitution after transplant. In Project 2, Jeffrey Miller discovered that NKG2C+ NK cells expand in vivo with CMV reactivation resulting in NK cells with specialized function through CD16 with enhanced cytokine responsiveness. He will test whether CMV-induced adaptive NK cells are better equipped to treat cancer compared to conventional NK cells. In Project 3, the clinical outlet of this Program, Daniel Weisdorf will 1) Use KIR typing for choosing favorable unrelated transplant donors, 2) Test NK cells in a randomized trial, and 3) Target NK cells specifically to AML and MDS by the use of bi-specific killer engagers (BiKEs). The research in the Projects will be supported by the Administration and Clinical Research Support (Core A), Biostatistics (Core B), our unique Bioinformatis and Data Management teams (Core C) and our Immune Moitoring and BiKE Production (Core D) resources. This Program will establish definitive roles for NK cells and their receptors in allogeneic transplantation with broader impact to all cancer therapy.

Public Health Relevance

Advanced cancer continues to be a major health problem in US and scientific advances suggest that manipulating the immune response may result in effective anti-tumor therapy. In this Program, we focus on innate immune Natural Killer cells that are genetically defined by receptors that interact with self-tissue proteins call human leukocyte antigens or HLA. While our main focus is in myeloid blood cancers, these studies will impact all cancer patients who receive anti-cancer antibodies that work in part through NK cells. We propose strategies to change the practice of medicine by using NK cell receptor genes to make treatment decisions, to specifically direct NK cells to their cancer targets, and to optimally stimulate NK cell activity in the body. This Program is comprised of outstanding basic, translational and clinical trials research. With an international group of experts in NK cell bioloy and cancer treatment, this Program will establish definitive roles for NK cells and their receptors in allogeneic transplantation with broader impact to all cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA111412-12
Application #
9254438
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (O1))
Program Officer
Merritt, William D
Project Start
2004-12-01
Project End
2021-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
12
Fiscal Year
2017
Total Cost
$1,658,614
Indirect Cost
$349,112
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
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
de Witte, Moniek A; Sarhan, Dhifaf; Davis, Zachary et al. (2018) Early Reconstitution of NK and ?? T Cells and Its Implication for the Design of Post-Transplant Immunotherapy. Biol Blood Marrow Transplant 24:1152-1162
Pugh, Jason L; Nemat-Gorgani, Neda; Norman, Paul J et al. (2018) Human NK Cells Downregulate Zap70 and Syk in Response to Prolonged Activation or DNA Damage. J Immunol 200:1146-1158
Cichocki, Frank; Wu, Cheng-Ying; Zhang, Bin et al. (2018) ARID5B regulates metabolic programming in human adaptive NK cells. J Exp Med 215:2379-2395
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

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