title: Heterologous prime/boost immunization with p53-based vaccines combined with toll-like receptor stimulation enhances tumor regression.
abstract: The p53 gene product is overexpressed in approximately 50% of cancers, making it an ideal target for cancer immunotherapy. We previously demonstrated that a modified vaccinia Ankara (MVA) vaccine expressing human p53 (MVA-p53) was moderately active when given as a homologous prime/boost in a human p53 knock in (Hupki) mouse model. We needed to improve upon the inefficient homologous boosting approach, because development of neutralizing immunity to the vaccine viral vector backbone suppresses its immunogenicity. To enhance specificity, we examined the combination of 2 different vaccine vectors provided in sequence as a heterologous prime/boost. Hupki mice were evaluated as a human p53 tolerant model to explore the capacity of heterologous p53 immunization to reject human p53-expressing tumors. We employed attenuated recombinant Listeria monocytogenes expressing human p53 (LmddA-LLO-p53) in addition to MVA-p53. Heterologous p53 immunization resulted in a significant increase in p53-specific CD8 and CD4 T cells compared with homologous single vector p53 immunization. Heterologous p53 immunization induced protection against tumor growth but had only a modest effect on established tumors. To enhance the immune response we used synthetic double-strand RNA (polyinsosinic:polycytidylic acid) and unmethylated CpG-containing oligodeoxynucleotide to activate the innate immune system via Toll-like receptors. Treatment of established tumor-bearing Hupki mice with polyinsosinic:polycytidylic acid and CpG-oligodeoxynucleotide in combination with heterologous p53 immunization resulted in enhanced tumor rejection relative to treatment with either agent alone. These results suggest that heterologous prime/boost immunization and Toll-like receptor stimulation increases the efficacy of a cancer vaccine, targeting a tolerized tumor antigen.
authors.affiliation: Division of General and Oncologic Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Ishizaki
authors.forename: Guang-Yun
authors.initials: GY
authors.lastname: Song
authors.forename: Tumul
authors.initials: T
authors.lastname: Srivastava
authors.forename: Kyla Driscoll
authors.initials: KD
authors.lastname: Carroll
authors.forename: Vafa
authors.initials: V
authors.lastname: Shahabi
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Manuel
authors.forename: Don J
authors.initials: DJ
authors.lastname: Diamond
authors.forename: Joshua D I
authors.initials: JD
authors.lastname: Ellenhorn
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005822:Genetic Vectors / Q000276:immunology; D006084:Graft Rejection; D006801:Humans; D007117:Immunization, Secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009838:Oligodeoxyribonucleotides / Q000276:immunology*; D012330:RNA, Double-Stranded / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051193:Toll-Like Receptors / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: C408982:CPG-oligonucleotide; D019496:Cancer Vaccines; D009838:Oligodeoxyribonucleotides; D012330:RNA, Double-Stranded; D051193:Toll-Like Receptors; D016159:Tumor Suppressor Protein p53