Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer.
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.
Stanislawski
T
T
Department of Hematology and Oncology, Johannes Gutenberg University, D-55101 Mainz, Germany.
Voss
R H
RH
Lotz
C
C
Sadovnikova
E
E
Willemsen
R A
RA
Kuball
J
J
Ruppert
T
T
Bolhuis
R L
RL
Melief
C J
CJ
Huber
C
C
Stauss
H J
HJ
Theobald
M
M
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D002460:Cell Line; D003601:Cytotoxicity Tests, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D019672:Genes, T-Cell Receptor; D015316:Genetic Therapy; D015789:HLA-A2 Antigen / Q000235:genetics; D006801:Humans; D016219:Immunotherapy, Adoptive; D007938:Leukemia / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000276:immunology*; D051736:Proto-Oncogene Proteins c-mdm2; D017634:Self Tolerance; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2