Project 3T cells, which normally function to monitor for aberrantly expressed intracellular antigens, are deleted duringdevelopment if they are autoreactive. Many tumorigenic mutations result in only minor deviations from self inthe epitopes presented to T cells by products of the major histocompatibility complex (MHC). Hence, the Tcell repertoire that remains after thymic development and selection consists largely of low-affinity receptorsagainst potential tumor antigens. To overcome this deficiency in the tumor-specific T cell repertoire, variouslabs have attempted to transfer genes that encode a tumor-specific a(3 T cell receptor into a patient's T cellsex vivo. In concert with these efforts, TCRs have been engineered for higher affinities against peptide/MHCantigens. Our principle hypothesis is that these high-affinity TCRs can be used to treat cancer, either inadoptive T cell therapies or as soluble targeting molecules (by analogy to monoclonal antibodies). Whilethese approaches show promise, significant questions remain regarding their optimal use. The purpose ofthis project is to address these questions, and thereby to interface with other projects in this program that willdirectly apply the findings to several different tumor models. The project will make use of our extensiveearlier studies in the mouse system involving CTL clone 2C, and a collection of 2C TCR mutants that havealready been engineered with a range of affinities.
The specific aims of the project that will be directed byDavid Kranz at the University of Illinois are:
Specific Aim 1. To examine the binding properties of TCR 2Cthat result in optimal specificity, peripheral expansion, survival, and activity of transduced T cells.
SpecificAim 2. To explore various strategies to increase the surface levels of exognous TCRs introduced by genetransduction.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA097296-06
Application #
7473378
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (J1))
Project Start
2008-07-31
Project End
2013-05-31
Budget Start
2008-07-31
Budget End
2009-05-31
Support Year
6
Fiscal Year
2008
Total Cost
$296,876
Indirect Cost
Name
University of Chicago
Department
Type
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Spaapen, Robbert M; Leung, Michael Y K; Fuertes, Mercedes B et al. (2014) Therapeutic activity of high-dose intratumoral IFN-? requires direct effect on the tumor vasculature. J Immunol 193:4254-60
Woo, Seng-Ryong; Fuertes, Mercedes B; Corrales, Leticia et al. (2014) STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41:830-42

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