Immunotoxins (IT) are experimental pharmacologic agents that are made by linking antibodies or cytokines that specifically bind to cancer cells to potent catalytic toxins of which a single molecule can kill a cell. Their major purpose is to deliver therapy selectively to cancer cells instead of non-target organs, as does conventional chemotherapy. Although these agents selectively bind and kill cancer cells, clinically they have been limited by their 1) failure to penetrate and localize in adequate concentrations in cancer target tissue 2) localization in nontarget organs limiting the tolerated dose and collapsing the therapeutic window. In this proposal, we will explore a solution to this problem. Cells of the immune system such as T cells are the most prominent cell types which penetrate, attack, and destroy cancer cells and are naturally suited for the expression and production of cytokines in response to antigenic challenge. Therefore, in the first cycle of funding we took advantage of the a well-known property of T cells which is their ability to migrate to tumors and provided proof that they could be used to deliver immunotoxin to leukemia in vivo using gene therapy. We showed that T cells could deliver retroviral IT (retlT) consisting of IL-3 spliced to genetically modified toxin locally at the site of the leukemia and produce a significant anti-leukemia effect. Our studies have now generated several important questions concerning this new class of agent, and in this proposal, we will attempt to determine how they work. We have established a new model of retlT therapy which we will use as a foundation for future attempts to modify and improve retlT. The model takes advantage of the use of antigen specific T cell clones. We will use this to test the usefulness of retlT leukemia therapy. Previous studies focused us on a single ligand (IL-3). Now, in aim 1 we will characterize the role of T cells in this established model, determining whether it is better to use CD4+ or CD8+ T cell clones for delivery. Then in aims 2, 3, and 4 we will determine just how and why our approach works.
Aim 2 will focus on the T cell component of the model and we will ask how many T cells localize to the tumor in vivo as compared to other extratumoral sites. Will the localization of T these retlT secreting T cells cause toxicity? Aim 3 focuses on the IT moiety and we will determine the role of secreted IT and how much is necessary. Finally in aim 4, we will determine if retlT can reduce toxicity compared to conventional IT and whether they have effects on components of the host immune system.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA082154-05
Application #
6761729
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Welch, Anthony R
Project Start
2000-04-01
Project End
2008-06-30
Budget Start
2004-08-18
Budget End
2005-06-30
Support Year
5
Fiscal Year
2004
Total Cost
$314,078
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Oh, Seunguk; Tsai, Alexander K; Ohlfest, John R et al. (2011) Evaluation of a bispecific biological drug designed to simultaneously target glioblastoma and its neovasculature in the brain. J Neurosurg 114:1662-71
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Oh, Seunguk; Stish, Brad J; Vickers, Selwyn M et al. (2010) A new drug delivery method of bispecific ligand-directed toxins, which reduces toxicity and promotes efficacy in a model of orthotopic pancreatic cancer. Pancreas 39:913-22
Stish, B J; Oh, S; Chen, H et al. (2009) Design and modification of EGF4KDEL 7Mut, a novel bispecific ligand-directed toxin, with decreased immunogenicity and potent anti-mesothelioma activity. Br J Cancer 101:1114-23
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Stish, Brad J; Oh, Seunguk; Vallera, Daniel A (2008) Anti-glioblastoma effect of a recombinant bispecific cytotoxin cotargeting human IL-13 and EGF receptors in a mouse xenograft model. J Neurooncol 87:51-61
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Stish, Brad J; Chen, Hua; Shu, Yanqun et al. (2007) Increasing anticarcinoma activity of an anti-erbB2 recombinant immunotoxin by the addition of an anti-EpCAM sFv. Clin Cancer Res 13:3058-67

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