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The Journal of Immunology, 2008, 181: 5128-5136.
Copyright © 2008 by The American Association of Immunologists, Inc.
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Requirements for Effective Antitumor Responses of TCR Transduced T Cells1

Moniek A. de Witte2, Annelies Jorritsma2, Andrew Kaiser, Marly D. van den Boom, Maarten Dokter, Gavin M. Bendle, John B. A. G. Haanen and Ton N. M. Schumacher3

Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, The Netherlands

Adoptive transfer of TCR gene-modified T cells has been proposed as an attractive approach to target tumors for which it is difficult or impossible to induce strong tumor-specific T cell responses by vaccination. Whereas the feasibility of generating tumor Ag-specific T cells by gene transfer has been demonstrated, the factors that determine the in vivo effectiveness of TCR-modified T cells are largely unknown. We have analyzed the value of a number of clinically feasible strategies to enhance the antitumor potential of TCR modified T cells. These experiments reveal three factors that contribute greatly to the in vivo potency of TCR-modified T cells. First, irradiation-induced host conditioning is superior to vaccine-induced activation of genetically modified T cells. Second, increasing TCR expression through genetic optimization of TCR sequences has a profound effect on in vivo antitumor activity. Third, a high precursor frequency of TCR modified T cells within the graft is essential. Tumors that ultimately progress in animals treated with this optimized regimen for TCR-based adoptive cell transfer invariably display a reduced expression of the target Ag. This suggests TCR gene therapy can achieve a sufficiently strong selective pressure to warrant the simultaneous targeting of multiple Ags. The strategies outlined in this study should be of value to enhance the antitumor activity of TCR-modified T cells in clinical trials.

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 research was supported by grants from the Dutch Cancer Society (NKI 2003-2860), the European Union Sixth Framework program (ATTACK), and ZON-MW (431-00-005).

2 M.A.d.W. and A.J. contributed equally to this work.

3 Address correspondence and reprint requests to: Dr. Ton N. M. Schumacher, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands. E-mail address: t.schumacher{at}nki.nl

4 Abbreviations used in this paper: ACT, adoptive cell therapy; TBI, total body irradiation; rVV-OVA, recombinant vaccinia strain that expresses OVA.






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