Abstract

Successful allogeneic hematopoietic cell transplantation (HCT) requires lymphopoietic recovery, control of graft vs. host disease (GVHD), and protection against relapse. Exploitationof NK cell reactivity requires understanding NK cell regulation through class I recognizing, killer immunoglohulin-like receptors (KIR) and algorithms for donor choice to maximize donor NK cell reactivity. We propose prospective clinical trials and analyses to target this reactivity.
Aim 1 will investigate KIR-ligand mismatched unrelated donor(URD) HCT of a partiallyT-cell depleted matched graft to control GVHD and enhance anti-leukemia effects. Acquisition of NK cells which escape alloinhibition (through inhibitory KIR) may improve outcome.
In Aim 2, 2 prospective analyses will test NK cell:KIR functional interaction on HCT outcome.
In Aim 2 a, we hypothesize that an activating KIR genotype and recovery of normal, donor pattern KIR expression will better protect against infection. Donor and recipient KIR genotype may predict infection risk.
Aim 2 b will prospectively evaluate differences in KIR genotype and expression in a prospective randomized trial of URD blood vs. bone marrow HCT. Donor and recipient KIR difference and expression will be tested for effects on risk of GVHD, infections, and relapse;differentiallyin PB or BM grafts. We will test 4 strategies for NK & KIR matching on outcome. The first two strategies depend only on HLA class I phenotype: 1) KIR-ligand mismatch;2) recipient KIR-ligand absence;using KIR genotyping in 3) recipient KIR-ligand: donor KIR gene cor tent;and using both KIR genotyping and expression on NK cells, 4) recipient KIR-ligand: recipient donor-derived KIR expression. Each may clarify the physiologic regulation of NK:host interaction.
Aim 3 will extend our work using haploidentical donor NK infusions in a clinical trial testing donor NK cells in a reduced intensity HCT. Donor NK infusions may deplete recipient dendritic cells, limit GVHD and aid in prevention of relapse. These studies, using KIR genotype and KIR expression data developed in Projects 1 and 2, will explore the clinical applicability of NK alloreactivity to improve the success;of allogeneic HCT.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA111412-05
Application #
7914183
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
5
Fiscal Year
2009
Total Cost
$624,666
Indirect Cost

  Institution

Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455

  Publications

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

Showing the most recent 10 out of 108 publications