title: CTLA-4 blockade enhances the therapeutic effect of an attenuated poxvirus vaccine targeting p53 in an established murine tumor model.
abstract: 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.
authors.affiliation: Division of General and Oncologic Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Espenschied
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lamont
authors.forename: Jeff
authors.initials: J
authors.lastname: Longmate
authors.forename: Solange
authors.initials: S
authors.lastname: Pendas
authors.forename: Zhongde
authors.initials: Z
authors.lastname: Wang
authors.forename: Don J
authors.initials: DJ
authors.lastname: Diamond
authors.forename: Joshua D I
authors.initials: JD
authors.lastname: Ellenhorn
mesh_terms: D000069594:Abatacept; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D002460:Cell Line; D006224:Cricetinae; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology / Q000401:mortality / Q000517:prevention & control; D005822:Genetic Vectors; D006801:Humans; D018796:Immunoconjugates; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology; D008212:Lymphocyte Depletion; D008748:Methylcholanthrene; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D012513:Sarcoma, Experimental / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics*; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology*; D014765:Viral Vaccines / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*
chemical_list: D000276:Adjuvants, Immunologic; D019138:Antibodies, Blocking; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D016159:Tumor Suppressor Protein p53; D014613:Vaccines, Attenuated; D014614:Vaccines, Synthetic; D014765:Viral Vaccines; D008748:Methylcholanthrene; D000069594:Abatacept; D007371:Interferon-gamma