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

• Published in: Nature immunology Vol. 2; no. 10; pp. 962 - 970
• Main Authors: Theobald, Matthias, Stanislawski, Thomas, Voss, Ralf-Holger, Lotz, Carina, Sadovnikova, Elena, Willemsen, Ralph A, Kuball, Jürgen, Ruppert, Thomas, Bolhuis, Reinder L. H, Melief, Cornelius J, Huber, Christoph, Stauss, Hans J
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.10.2001
• Subjects: Animals; Antigen (tumor-associated); Antigens; Antigens, Neoplasm - immunology; Avidity; Cell Line; Cytotoxicity; Cytotoxicity Tests, Immunologic; Epitopes; Epitopes, T-Lymphocyte - immunology; Gene transfer; Genes, T-Cell Receptor; Genetic Therapy; Histocompatibility antigen HLA; HLA-A2 Antigen - genetics; Humans; Immunological tolerance; Immunotherapy; Immunotherapy, Adoptive; Leukemia - immunology; Leukemia - therapy; Lymphocytes; Lymphocytes T; MDM2 protein; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms - immunology; Neoplasms - therapy; Nuclear Proteins; Proto-Oncogene Proteins - immunology; Proto-Oncogene Proteins c-mdm2; Rodents; Self Tolerance; T cell receptors; T-Lymphocytes, Cytotoxic - immunology; Transduction, Genetic; Transgenic animals; Transgenic mice; Tumor Cells, Cultured; Tumors
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni1001-962

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.