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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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Submitted May 12, 2006
Accepted October 28, 2006
Facilitating matched pairing and expression of TCR-chains introduced into human T-cells
Jurgen Kuball*, Michelle L Dossett, Matthias Wolfl, William Y Ho, Ralf-Holger Voss, Carla Fowler, and Philip D Greenberg
Fred Hutchinson Cancer Research Center, United States
Dept of Immunology, University of Washington School of Medicine, United States
University of Mainz, Germany
* Corresponding author; email: j.kuball{at}gmx.de.
Adoptive transfer of T-lymphocytes is a promising treatment for a variety of malignancies, but often not feasible due to difficulties generating T-cells 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  chains of an antigen-specific T-cell receptor (TCR). However, such exogenous and chains can potentially assemble as pairs not only with each other but with endogenous TCR and chains, thereby generating TCR-pairs of unknown specificity as well as reducing the number of exogenous matched TCR-pairs at the cell surface. We demonstrate that introducing cysteines into the constant region of the and 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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