Allogeneic bone marrow transplantation (BMT) is currently used for the treatment of a variety of cancers but graft-versus host disease (GVHD), immune deficiency following the transplant, and relapse remain significant obstacles limiting efficacy. Development of a means to improve the anti-tumor effects of BMT is of considerable importance. Natural killer (NK) cells have been shown to mediate numerous anti-tumor effects both in vivo and in vitro. We have previously demonstrated that donor-type NK cells can prevent GVHD and promote anti-tumor effects following allogeneic BMT in mice. NK cells can be regulated, both in positive and negative manners by a variety of mediators. This proposal will develop means to optimize NK cell recovery and activity following allogeneic BMT resulting in greater anti-tumor effects. To do this three specific aims are proposed:
Specific Aim 1 will build on our recent data demonstrating that regulatory T (Tregs) cells can suppress NK activity. We propose to determine the mechanism(s) underlying this suppression and to ascertain the effects of Treg depletion on NK reconstitution and activity following allogeneic BMT.
Specific Aim 2 will then seek to accelerate donor NK cell recovery post-BMT through the use of hydrodynamic gene delivery of IL15. Effects on GVHD, donor reconstitution as well as anti-tumor effects will be determined.
Specific Aim 3 will determine the role of NK cell subpopulations on donor recovery, GVHD protection, and anti-tumor effects by building on our data that the interactions between these subsets result in significant effects on activity in vivo. The data obtained from this proposal should yield significant insights into NK cell biology as well as allowing the development of approaches that result in superior anti-tumor effects.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089905-05
Application #
7860391
Study Section
Special Emphasis Panel (ZRG1-CII-V (01))
Program Officer
Wagner, Elizabeth
Project Start
2007-07-18
Project End
2011-12-14
Budget Start
2010-06-01
Budget End
2011-12-14
Support Year
5
Fiscal Year
2010
Total Cost
$382,500
Indirect Cost
Name
University of California Davis
Department
Dermatology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Luna, Jesus I; Grossenbacher, Steven K; Murphy, William J et al. (2017) Targeting Cancer Stem Cells with Natural Killer Cell Immunotherapy. Expert Opin Biol Ther 17:313-324
Alvarez, Maite; Sun, Kai; Murphy, William J (2016) Mouse host unlicensed NK cells promote donor allogeneic bone marrow engraftment. Blood 127:1202-5
Grossenbacher, Steven K; Canter, Robert J; Murphy, William J (2016) Natural killer cell immunotherapy to target stem-like tumor cells. J Immunother Cancer 4:19
Ames, Erik; Canter, Robert J; Grossenbacher, Steven K et al. (2015) NK Cells Preferentially Target Tumor Cells with a Cancer Stem Cell Phenotype. J Immunol 195:4010-9
Ames, Erik; Canter, Robert J; Grossenbacher, Steven K et al. (2015) Enhanced targeting of stem-like solid tumor cells with radiation and natural killer cells. Oncoimmunology 4:e1036212
Zamora, Anthony E; Grossenbacher, Steven K; Aguilar, Ethan G et al. (2015) Models to Study NK Cell Biology and Possible Clinical Application. Curr Protoc Immunol 110:14.37.1-14
Sungur, Can M; Murphy, William J (2014) Positive and negative regulation by NK cells in cancer. Crit Rev Oncog 19:57-66
Alvarez, Maite; Bouchlaka, Myriam N; Sckisel, Gail D et al. (2014) Increased antitumor effects using IL-2 with anti-TGF-? reveals competition between mouse NK and CD8 T cells. J Immunol 193:1709-16
Ames, Erik; Murphy, William J (2014) Advantages and clinical applications of natural killer cells in cancer immunotherapy. Cancer Immunol Immunother 63:21-8
Ames, Erik; Murphy, William J (2014) The authors' reply. Transplantation 98:e39-40

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