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Blood, 15 March 2007, Vol. 109, No. 6, pp. 2331-2338.
Prepublished online as a Blood First Edition Paper on November 2, 2006; DOI 10.1182/blood-2006-05-023069.
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GENE THERAPY
Facilitating matched pairing and expression of TCR chains introduced into human T cells
Jürgen Kuball1,2,
Michelle L. Dossett1,2,
Matthias Wolfl1,2,
William Y. Ho1,2,
Ralf-Holger Voss3,
Carla Fowler1,2, and
Philip D. Greenberg1,2
1 The Fred Hutchinson Cancer Research Center, Program in Immunology, Seattle, WA;
2 Department of Immunology, University of Washington School of Medicine, Seattle, WA;
3 Department of Hematology and Oncology, University of Mainz, Germany
Adoptive transfer of T lymphocytes is a promising treatment for a variety of malignancies but often not feasible due to difficulties generating T cells that are reactive with the targeted antigen from patients. To facilitate rapid generation of cells for therapy, T cells can be programmed with genes encoding the  and ß chains of an antigen-specific T-cell receptor (TCR). However, such exogenous and ß chains can potentially assemble as pairs not only with each other but also with endogenous TCR and ß chains, thereby generating ßTCR pairs of unknown specificity as well as reducing the number of exogenous matched ßTCR pairs at the cell surface. We demonstrate that introducing cysteines into the constant region of the and ß chains can promote preferential pairing with each other, increase total surface expression of the introduced TCR chains, and reduce mismatching with endogenous TCR chains. This approach should improve both the efficacy and safety of ongoing efforts to use TCR transfer as a strategy to generate tumor-reactive T cells.
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