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Dual T Cell Receptor Expressing CD8⁺ T Cells with Tumor- and Self-Specificity Can Inhibit Tumor Growth without Causing Severe Autoimmunity¹

Monika Weinhold^*,, Daniel Sommermeyer, Wolfgang Uckert^, and Thomas Blankenstein^2,*,

^* Institute of Immunology, Charité, Hindenburgdamm 30, Berlin, Germany; Max-Delbrück-Center for Molecular Medicine, Berlin, Germany; and Institute of Biology, Humboldt University Berlin, Berlin, Germany

The engineering of Ag-specific T cells by expression of TCR genes is a convenient method for adoptive T cell immunotherapy. A potential problem is the TCR gene transfer into self-reactive T cells that survived tolerance mechanisms. We have developed an experimental system with T cells that express two TCRs with defined Ag-specificities, one recognizing a tumor-specific Ag (LCMV-gp₃₃), the other recognizing a self-Ag in the pancreas (OVA). By using tumor cells expressing high and low amounts of Ag and mice expressing high and low levels of self-Ag in the pancreas (RIP-OVA-Hi and RIP-OVA-Lo), we show that 1) tumor rejection requires high amount of tumor Ag, 2) severe autoimmunity requires high amount of self-Ag, and 3) if Ag expression on tumor cells is sufficient and low in the pancreas, successful adoptive T cell therapy can be obtained in the absence of severe autoimmunity. These results are shown with T cells from dual TCR transgenic mice or T cells that were redirected by TCR gene transfer. Our data demonstrate that the approach of adoptively transferring TCR redirected T cells can be effective without severe side effects, even when high numbers of T cells with self-reactivity were transferred.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by grants from the Sixth Framework Programme (ATTACK 18914) and Deutsche Forschungsgemeinschaft (Sonderforschungsbereich TR36).

² Address correspondence and reprint requests to Dr. Thomas Blankenstein, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle Str. 10, Berlin, Germany. E-mail address: tblanke{at}mdc-berlin.de

³ Abbreviations used in this paper: Stg, single TCR transgenic; Dtg, dual TCR transgenic; BG, blood glucose; LCMV, Lymphocyte choriomeningitis virus; T_E, effector T cells.