An MVA vaccine overcomes tolerance to human p53 in mice and humans.
BACKGROUND
The cellular regulatory protein p53 is overexpressed by almost 50% of all malignancies making it an attractive target for a vaccine approach to cancer. A number of immunotherapy approaches targeting p53 have been evaluated successfully in murine models, but translation of these preclinical findings to the clinic has been unsuccessful. Prior studies in our laboratory employing murine models demonstrated that a modified vaccinia virus Ankara (MVA) vaccine expressing murine p53 could stimulate p53 specific immunity. Systemic administration of the MVA vaccine was able to effect the rejection of established tumors. To better understand the immunologic mechanisms that underlie the vaccine function of human p53, we utilized a murine model in which the murine germ line copy of p53 was replaced with a modified human one. These mice, referred to as Hupki, were evaluated as a tolerant model to explore the capacity of MVA expressing human p53 to overcome tolerance and reject human p53-expressing tumors.


RESULTS
MVAp53 immunization of Hupki mice resulted in the generation of p53-specific CD8(+) T cells and the rejection of a highly aggressive murine mammary carcinoma cell line 4T1(H-2d) transfected with human p53 (4T1p53). An immunologic correlate of tumor protection was evaluated utilizing an overlapping peptide library spanning the full length of human p53. This reagent was also used in combination with MVAp53 to stimulate p53-specific CD8(+) T cell responses in cancer patients.


CONCLUSIONS
These studies demonstrate the potential of MVAp53 to overcome tolerance to p53 for cancer immunotherapy.
Song
Guang-Yun
GY
Department of General and Oncologic Surgery, City of Hope National Medical Center, Duarte, CA, USA.
Gibson
Glen
G
Haq
Wahajul
W
Huang
Eric C C
EC
Srivasta
Tumul
T
Hollstein
Monica
M
Daftarian
Pirouz
P
Wang
Zhongde
Z
Diamond
Don
D
Ellenhorn
Joshua D I
JD
D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000276:immunology; D002478:Cells, Cultured / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006258:Head and Neck Neoplasms / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D016233:Immunotherapy, Active; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; C521519:MVAp53 vaccine; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; D007371:Interferon-gamma