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

Thomas Stanislawski, Ralf Holger Voss, Carina Lotz, Elena Sadovnikova, Ralph A. Willemsen, Jürgen Kuball, Thomas Ruppert, Reinder L.H. Bolhuis, Cornelius J. Melief, Christoph Huber, Hans J. Stauss, Matthias Theobald*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

298 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)962-970
Number of pages9
JournalNature immunology
Volume2
Issue number10
DOIs
Publication statusPublished - 29 Oct 2001

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