Engineering T Cell Receptors for Optimal Targeting of Established Tumors

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