title: Development of oral cancer vaccine using recombinant Bifidobacterium displaying Wilms' tumor 1 protein.
abstract: Several types of vaccine-delivering tumor-associated antigens (TAAs) have been developed in basic and clinical research. Wilms' tumor 1 (WT1), identified as a gene responsible for pediatric renal neoplasm, is one of the most promising TAA for cancer immunotherapy. Peptide and dendritic cell-based WT1 cancer vaccines showed some therapeutic efficacy in clinical and pre-clinical studies but as yet no oral WT1 vaccine can be administrated in a simple and easy way. In the present study, we constructed a novel oral cancer vaccine using a recombinant Bifidobacterium longum displaying WT1 protein. B. longum 420 was orally administered into mice inoculated with WT1-expressing tumor cells for 4 weeks to examine anti-tumor effects. To analyze the WT1-specific cellular immune responses to oral B. longum 420, mice splenocytes were isolated and cytokine production and cytotoxic activities were determined. Oral administrations of B. longum 420 significantly inhibited WT1-expressing tumor growth and prolonged survival in mice. Immunohistochemical study and immunological assays revealed that B. longum 420 substantially induced tumor infiltration of CD4+T and CD8+T cells, systemic WT1-specific cytokine production, and cytotoxic activity mediated by WT1-epitope specific cytotoxic T lymphocytes, with no apparent adverse effects. Our novel oral cancer vaccine safely induced WT1-specific cellular immunity via activation of the gut mucosal immune system and achieved therapeutic efficacy with several practical advantages over existing non-oral vaccines.
authors.affiliation: Division of Translational Research for Biologics, Department of Internal Related, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kitagawa
authors.affiliation: Department of International Health, Kobe University Graduate School of Health Sciences, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Tsugumi
authors.initials: T
authors.lastname: Oda
authors.affiliation: Division of Translational Research for Biologics, Department of Internal Related, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Saito
authors.affiliation: Department of International Health, Kobe University Graduate School of Health Sciences, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Ayame
authors.initials: A
authors.lastname: Araki
authors.affiliation: Division of Advanced Medical Science, Kobe University Graduate School of Science, Technology and Innovation, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Reina
authors.initials: R
authors.lastname: Gonoi
authors.affiliation: Division of Urology, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Shigemura
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2, Yamada-Oka, Suita, Osaka, 565-0871, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Hashii
authors.affiliation: Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Yoshida-honmachi, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Takane
authors.initials: T
authors.lastname: Katayama
authors.affiliation: Division of Urology, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Fujisawa
authors.affiliation: Division of Translational Research for Biologics, Department of Internal Related, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. toshiro@med.kobe-u.ac.jp.|Department of International Health, Kobe University Graduate School of Health Sciences, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. toshiro@med.kobe-u.ac.jp.|Division of Advanced Medical Science, Kobe University Graduate School of Science, Technology and Innovation, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. toshiro@med.kobe-u.ac.jp.|Division of Urology, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. toshiro@med.kobe-u.ac.jp.
authors.forename: Toshiro
authors.identifier: http://orcid.org/0000-0003-3925-8730
authors.initials: T
authors.lastname: Shirakawa
mesh_terms: D000818:Animals; D001644:Bifidobacterium / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D005260:Female; D007167:Immunotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009062:Mouth Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000628:therapy*; D015996:Survival Rate; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D025721:WT1 Proteins / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D025721:WT1 Proteins
keywords: Bifidobacterium; Cancer vaccine; Immunotherapy; Oral vaccine; WT1