An MVA vaccine overcomes tolerance to human p53 in mice and humans

Guang Yun Song, Glen Gibson, Wahajul Haq, Eric C C Huang, Tumul Srivasta, Monica Hollstein, Pirouz Daftarian, Zhongde Wang, Don Diamond, Joshua D I Ellenhorn

Research output: Contribution to journalArticle

Abstract

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. Conclusion: These studies demonstrate the potential of MVAp53 to overcome tolerance to p53 for cancer immunotherapy.

Original languageEnglish (US)
Pages (from-to)1193-1205
Number of pages13
JournalCancer Immunology Immunotherapy
Volume56
Issue number8
DOIs
Publication statusPublished - Aug 2007
Externally publishedYes

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Keywords

  • Animal models of cancer
  • Cancer vaccines
  • Immune response to cancer
  • p53

ASJC Scopus subject areas

  • Cancer Research
  • Immunology
  • Oncology

Cite this

Song, G. Y., Gibson, G., Haq, W., Huang, E. C. C., Srivasta, T., Hollstein, M., ... Ellenhorn, J. D. I. (2007). An MVA vaccine overcomes tolerance to human p53 in mice and humans. Cancer Immunology Immunotherapy, 56(8), 1193-1205. https://doi.org/10.1007/s00262-006-0270-3