title: A novel adenovirus expressing human 4-1BB ligand enhances antitumor immunity.
abstract: 4-1BB ligand (4-1BBL), a member of the tumor necrosis factor (TNF) superfamily, interacts with 4-1BB (CDw137) expressed on activated T cells and delivers a costimulatory signal for T cell activation and growth. Various studies have demonstrated a role for murine 4-1BB in immune function, but relatively few investigations of human 4-1BB have been conducted. Here we report on the construction of a recombinant E1/E3-deleted adenovirus encoding human 4-1BBL (Ad4-1BBL) and its stimulation of antitumor immunity. Ad4-1BBL was able to efficiently infect several human adenocarcinoma cell lines and induce 4-1BBL expression on the cell surface within 24 h, this enhancing the antitumor activity not only of lymphokine-activated killer cells with a T cell phenotype (T-LAK) but also naive peripheral blood mononuclear cells (PBMC). This antitumor activity with T-LAK cells was further enhanced by addition of bispecific antibody (BsAb; anti-MUC1xanti-CD3). Cocultivation of Ad4-1BBL-infected tumor cells with either T-LAK cells or PBMC resulted in significant elevation of interferon-gamma (IFN-gamma), interleukin-2 (IL-2), and granulocyte-macrophage colony-stimulating factor (GM-CSF) production. Furthermore, remarkable tumor growth inhibition was observed in cholangiocarcinoma-grafted severe combined immunodeficient (SCID) mice to which Ad4-1BBL and T-LAK cells were administered when tumor size exceeded 5 mm in diameter. These results provide strong evidence in support of the efficacy of adenovirally delivered 4-1BBL for genetic immunotherapy of cancer.
authors.affiliation: Department of Surgery, Division of Gastroenterological Surgery, Tohoku University Graduate School of Medicine, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Yu
authors.initials: Y
authors.lastname: Katayose
authors.forename: Michiaki
authors.initials: M
authors.lastname: Unno
authors.forename: Masanori
authors.initials: M
authors.lastname: Suzuki
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kodama
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Takemura
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Asano
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hayashi
authors.forename: Kuniharu
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Seiki
authors.initials: S
authors.lastname: Matsuno
authors.forename: Toshio
authors.initials: T
authors.lastname: Kudo
mesh_terms: D053330:4-1BB Ligand; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D018033:Antibodies, Bispecific / Q000627:therapeutic use; D015703:Antigens, CD; D001650:Bile Duct Neoplasms / Q000628:therapy; D001653:Bile Ducts, Intrahepatic; D017252:CD3 Complex / Q000276:immunology; D018281:Cholangiocarcinoma / Q000276:immunology / Q000628:therapy*; D015316:Genetic Therapy; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D018396:Mucin-1 / Q000276:immunology; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000628:therapy; D017475:Receptors, Nerve Growth Factor / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D014407:Tumor Cells, Cultured; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000502:physiology
chemical_list: D053330:4-1BB Ligand; D018033:Antibodies, Bispecific; D015703:Antigens, CD; D017252:CD3 Complex; D007376:Interleukin-2; D018396:Mucin-1; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505714:TNFRSF9 protein, human; C505974:TNFSF9 protein, human; C505715:Tnfrsf9 protein, mouse; C505975:Tnfsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor