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T Cell Receptors For Potential Cancer Immunotherapy Applications

T Cell Receptors For Potential Cancer Immunotherapy Applications: Single Chain T Cell Receptors Circumvent Mispairing with Endogenous TCR and Mediate T Cell Activity Friday, April 6, 2012 • 10:05-10:20 AM Authors: David H. Aggen*, Adam S. Chervin, Carolina M. Soto, Thomas M. Schmitt, Boris Engels, Jennifer D. Stone, Sarah A. Richman, Kurt H. Piepenbrink, Brian M. Baker, Philip D. Greenberg, Hans Schreiber, and David M. Kranz To improve the immune response to cancer, gene therapy with tumor-specific T cell-receptors (TCRs) provides an attractive approach to effectively arm patients T cells for tumor cell destruction. A high-affinity TCR specific for an antigenic peptide-major histocompatibility complex (pepMHC) can be introduced into patients T cells in vitro, and transfer of transduced T cells could kill cancer cells. The promise of this approach is potentially hindered by mispairing of exogenous TCR chains with endogenous TCR chains that could generate mixed TCR-heterodimers with graft-vs-host specificities. To address the issue of 'mixed' TCR-heterodimers, we investigated the use of single-chain-TCRs (scTv) that lack constant-domains to avoid mispairing and compared activity of T cells expressing scTv relative to full-length TCR in vitro and in a murine tumor model. We demonstrated that the murine scTv m33, specific for a model tumor antigen pepMHC, mediated the activity of both CD4+ and CD8+ T cells with similar sensitivity to full-length m33 TCR. The scTv avoided mispairing with endogenous alpha-beta full-length TCRs and allowed for endogenous TCR surface expression at high levels. In a murine tumor model, CD8+ m33 scTv T cells persisted, whereas CD8+ m33 full-length TCR T cells were deleted, presumably by peripheral tolerance mechanisms.