CTLA-4 Blockade Enhances the Therapeutic Effect of an Attenuated Poxvirus Vaccine Targeting p53 in an Established Murine Tumor Model

• Published in: The Journal of immunology (1950) 2003-03, Vol.170 (6), p.3401-3407
• Main Authors: Espenschied, Jonathan, Lamont, Jeffrey, Longmate, Jeff, Pendas, Solange, Wang, Zhongde, Diamond, Don J, Ellenhorn, Joshua D. I
• Format: Article
• Language: English
• Subjects: Abatacept; Adjuvants, Immunologic - pharmacology; Animals; Antibodies, Blocking - pharmacology; Antigens, CD; Antigens, Differentiation - immunology; Cancer Vaccines - genetics; Cancer Vaccines - immunology; Cancer Vaccines - therapeutic use; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Line; Cricetinae; CTLA-4 Antigen; Female; Fibrosarcoma - immunology; Fibrosarcoma - mortality; Fibrosarcoma - prevention & control; Genetic Vectors; Humans; Immunoconjugates; Interferon-gamma - deficiency; Interferon-gamma - genetics; Interferon-gamma - physiology; Killer Cells, Natural - immunology; Lymphocyte Depletion; Methylcholanthrene; Mice; Mice, Inbred BALB C; Mice, Knockout; Sarcoma, Experimental - immunology; Sarcoma, Experimental - mortality; Sarcoma, Experimental - prevention & control; T-Lymphocytes, Cytotoxic - immunology; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - biosynthesis; Tumor Suppressor Protein p53 - genetics; Vaccines, Attenuated - genetics; Vaccines, Attenuated - immunology; Vaccines, Attenuated - therapeutic use; Vaccines, Synthetic - genetics; Vaccines, Synthetic - immunology; Vaccines, Synthetic - therapeutic use; Vaccinia virus - genetics; Vaccinia virus - immunology; Viral Vaccines - genetics; Viral Vaccines - immunology; Viral Vaccines - therapeutic use
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.170.6.3401

p53 is overexpressed by half of all cancers, and is an attractive target for a vaccine approach to immunotherapy. p53 overexpression is frequently the result of point mutations, which leaves the majority of the protein in its wild-type form. Therefore, the majority of p53 sequence is wild type, making it a self-protein for which tolerance plays a role in limiting immune responses. To overcome tolerance to p53, we have expressed wild-type murine p53 in the nonpathogenic attenuated poxvirus, modified vaccinia virus Ankara (recombinant modified vaccinia virus Ankara expressing wild-type murine p53 (rMVAp53)). Mice immunized with rMVAp53 vaccine developed vigorous p53-specific CTL responses. rMVAp53 vaccine was evaluated for its ability to inhibit the outgrowth of the syngeneic murine sarcoma Meth A, which overexpresses mutant p53. Mice were inoculated with a lethal dose (5 x 10(5) cells injected s.c.) of Meth A tumor cells and vaccinated by i.p. injection 3 days later with 5 x 10(7) PFU of rMVAp53. The majority of mice remained tumor free and resistant to rechallenge with Meth A tumor cells. We wished to determine whether rMVAp53 immunization could effect the rejection of an established, palpable Meth A tumor. In subsequent experiments, mice were injected with 10(6) Meth A tumor cells, and treated 6 days later with anti-CTLA-4 Ab (9H10) and rMVAp53. The majority of treated mice had complete tumor regression along with lasting tumor immunity. In vivo Ab depletion confirmed that the antitumor effect was primarily CD8 and to a lesser extent CD4 dependent. These experiments demonstrate the potential of a novel cell-free vaccine targeting p53 in malignancy.