Detection and eradication of minimal residual malignant disease is a major goal in cancer therapeutics. Nowhere is this more important than following hematopoietic cell transplantation (HCT) where the vast majority of patients are rendered to a state of minimal disease yet a significant percentage of patients will ultimately relapse. We have developed a novel animal model system to study both the fate, distribution and survival of minimal numbers of cancer cells and track immunological effector cell populations capable of controlling disease. To accomplish this goal we have introduced the luciferase (luc) gene into either the tumor or lymphoid populations of cells which can be tracked in vivo by light emission. Novel fusion genes have been constructed combining the green or yellow fluorescent proteins (gfp or yfp) which can be utilized for cell sorting and immunohistochemistry with that of luc which allows for in vivo imaging. Using this model system as few as 1,000 cells can be visualized, quantitated and tracked in living animals non-invasively. We have demonstrated that the amount of light emission is a quantitative measurement of tumor burden. The temporal and spatial assessment of disease progression and metastasis as well as response to therapy can be quantitatively, non-invasively assessed in real time. We will utilize models of both myeloablative and nonmyeloablative HCT to evaluate the role of these therapies in controlling minimal residual disease and affecting the development of graft vs host disease (GVHD). Lymphoid populations of cells will be evaluated for their ability to control minimal residual disease, suppress GVHD and enhance donor-specific engraftment. The gfp/luc fusion gene will be introduced into lymphoid effector cell populations to evaluate cell trafficking, survival and recovery of functionally active effector cells at sites of tumor or GVHD. The role, impact on T cell function and trafficking and in vivo fate of CD4+CD25 +T cells will be explored based upon our recent observations that these regulatory T cells are capable of suppressing GVHD while not impacting graft vs. tumor activity. Effector cells from selected knock-out strains and animals deficient in key molecules will be utilized to explore mechanisms of these diverse biological effects. These studies will provide important biological insights into the function of T cells in the control of malignant disease, suppression of GVHD and facilitation of engraftment. These insights will be utilized to develop strategies translatable to the clinic to improve outcomes for patients with a broad range of malignant conditions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA080006-05
Application #
6710692
Study Section
Special Emphasis Panel (ZRG1-ET-1 (02))
Program Officer
Yovandich, Jason L
Project Start
1999-05-01
Project End
2008-02-29
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
5
Fiscal Year
2004
Total Cost
$240,231
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Schneidawind, Dominik; Pierini, Antonio; Negrin, Robert S (2013) Regulatory T cells and natural killer T cells for modulation of GVHD following allogeneic hematopoietic cell transplantation. Blood 122:3116-21
Nishimura, Ryosei; Baker, Jeanette; Beilhack, Andreas et al. (2008) In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activity. Blood 112:2563-74
Beilhack, Andreas; Schulz, Stephan; Baker, Jeanette et al. (2008) Prevention of acute graft-versus-host disease by blocking T-cell entry to secondary lymphoid organs. Blood 111:2919-28
Bjorck, Pia; Beilhack, Andreas; Herman, Edward I et al. (2008) Plasmacytoid dendritic cells take up opsonized antigen leading to CD4+ and CD8+ T cell activation in vivo. J Immunol 181:3811-7
Kornacker, M; Verneris, Mr; Kornacker, B et al. (2006) The apoptotic and proliferative fate of cytokine-induced killer cells after redirection to tumor cells with bispecific Ab. Cytotherapy 8:13-23
Karimi, Mobin; Cao, Thai M; Baker, Jeanette A et al. (2005) Silencing human NKG2D, DAP10, and DAP12 reduces cytotoxicity of activated CD8+ T cells and NK cells. J Immunol 175:7819-28
Verneris, Michael R; Arshi, Arash; Edinger, Matthias et al. (2005) Low levels of Her2/neu expressed by Ewing's family tumor cell lines can redirect cytokine-induced killer cells. Clin Cancer Res 11:4561-70
Beilhack, Andreas; Schulz, Stephan; Baker, Jeanette et al. (2005) In vivo analyses of early events in acute graft-versus-host disease reveal sequential infiltration of T-cell subsets. Blood 106:1113-22
Cao, Yu-An; Bachmann, Michael H; Beilhack, Andreas et al. (2005) Molecular imaging using labeled donor tissues reveals patterns of engraftment, rejection, and survival in transplantation. Transplantation 80:134-9
Edinger, Matthias; Cao, Yu-An; Verneris, Michael R et al. (2003) Revealing lymphoma growth and the efficacy of immune cell therapies using in vivo bioluminescence imaging. Blood 101:640-8

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