title: Tumor-specific delivery of biologics by a novel T-cell line HOZOT.
abstract: "Cell-in-cell" denotes an invasive phenotype in which one cell actively internalizes in another. The novel human T-cell line HOZOT, established from human umbilical cord blood, was shown to penetrate a variety of human cancer cells but not normal cells. Oncolytic viruses are emerging as biological therapies for human cancers; however, efficient viral delivery is limited by a lack of tumor-specific homing and presence of pre-existing or therapy-induced neutralizing antibodies. Here, we report a new, intriguing approach using HOZOT cells to transmit biologics such as oncolytic viruses into human cancer cells by cell-in-cell invasion. HOZOT cells were successfully loaded via human CD46 antigen with an attenuated adenovirus containing the fiber protein of adenovirus serotype 35 (OBP-401/F35), in which the telomerase promoter regulates viral replication. OBP-401/F35-loaded HOZOT cells were efficiently internalized into human cancer cells and exhibited tumor-specific killing by release of viruses, even in the presence of anti-viral neutralizing antibodies. Moreover, intraperitoneal administration of HOZOT cells loaded with OBP-401/F35 significantly suppressed peritoneally disseminated tumor growth in mice. This unique cell-in-cell property provides a platform for selective delivery of biologics into human cancer cells, which has important implications for the treatment of human cancers.
authors.affiliation: Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Onishi
authors.affiliation: Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.|Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama 700-8558, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tazawa
authors.affiliation: Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Yuuri
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: R&D Center, Hayashibara Co., Ltd., Okayama 702-8006, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Takeuchi
authors.affiliation: R&D Center, Hayashibara Co., Ltd., Okayama 702-8006, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Otani
authors.affiliation: R&D Center, Hayashibara Co., Ltd., Okayama 702-8006, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
authors.forename: Fuminori
authors.initials: F
authors.lastname: Sakurai
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizuguchi
authors.affiliation: Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kishimoto
authors.affiliation: Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Umeda
authors.affiliation: Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shirakawa
authors.affiliation: Oncolys BioPharma, Inc., Tokyo 106-0032, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Urata
authors.affiliation: Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kagawa
authors.affiliation: Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Toshiyoshi
authors.initials: T
authors.lastname: Fujiwara
mesh_terms: D045744:Cell Line, Tumor; D005822:Genetic Vectors; D006801:Humans; D051916:Membrane Cofactor Protein; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses; D013601:T-Lymphocytes / Q000821:virology*
chemical_list: C497857:CD46 protein, human; D051916:Membrane Cofactor Protein