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

We identified a tumor-associated cytotoxic T lymphocyte (CTL) epitope deriv ed 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 th e A2.1-presented MDM2 epitope. Whereas the self-A2.1-restricted human T cel l repertoire gave rise only to low-avidity CTLs unable to recognize the nat ural MDM2 peptide, human A2.1(+) T lymphocytes were turned into efficient M DM2-specific CTLs upon expression of wild-type and partially humanized high -affinity T cell antigen receptor (TCR) genes derived from the transgenic m ice. These results demonstrate that TCR gene transfer can be used to circum vent self-tolerance of autologous T lymphocytes to universal tumor antigens and thus provide the basis for a TCR gene transfer-based broad-spectrum im munotherapy of malignant disease.