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Article
Nature Immunology  2, 962 - 970 (2001)
Published online: 1 October 2001; | doi:10.1038/ni1001-962

Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer

Thomas Stanislawski1, 6, Ralf-Holger Voss1, 6, Carina Lotz1, Elena Sadovnikova2, 7, Ralph A. Willemsen3, Jürgen Kuball1, Thomas Ruppert4, 8, Reinder L. H. Bolhuis3, Cornelius J. Melief5, Christoph Huber1, Hans J. Stauss2 & Matthias Theobald1

1  Department of Hematology and Oncology, Johannes Gutenberg University, D-55101 Mainz, Germany.

2  Department of Immunology, Hammersmith Hospital, Imperial College School of Medicine, London W12 0NN, UK.

3  Department of Clinical and Tumor Immunology, Daniel den Hoed Cancer Center, 3075 EA Rotterdam, The Netherlands.

4  Max von Pettenkofer Institute for Virology, Ludwig Maximilians University, D-80336 Munich, Germany.

5  Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.

6  These authors contributed equally to this work.

7  Present address: National Center for Hematology, 125167 Moscow, Russia.

8  Present address: Zentrum für Molekulare Biologie, Ruprecht-Karls University, D-69120 Heidelberg, Germany.

Correspondence should be addressed to Matthias Theobald m.theobald@3-med.klinik.uni-mainz.de
We identified a tumor-associated cytotoxic T lymphocyte (CTL) epitope derived from the widely expressed human MDM2 oncoprotein and were able to bypass self-tolerance to this tumor antigen in HLA-A*0201 (A2.1) transgenic mice and by generating A2.1-negative, allo-A2.1−restricted human T lymphocytes. A broad range of malignant, as opposed to nontransformed cells, were killed by high-avidity transgenic mouse and allogeneic human CTLs specific for the A2.1-presented MDM2 epitope. Whereas the self-A2.1−restricted human T cell repertoire gave rise only to low-avidity CTLs unable to recognize the natural MDM2 peptide, human A2.1+ T lymphocytes were turned into efficient MDM2-specific CTLs upon expression of wild-type and partially humanized high-affinity T cell antigen receptor (TCR) genes derived from the transgenic mice. These results demonstrate that TCR gene transfer can be used to circumvent self-tolerance of autologous T lymphocytes to universal tumor antigens and thus provide the basis for a TCR gene transfer−based broad-spectrum immunotherapy of malignant disease.

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Nature Immunology
ISSN: 1529-2908
EISSN: 1529-2916
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