title: Active immunotherapy induces antibody responses that target tumor angiogenesis.
abstract: The inhibition of VEGF signaling with antibodies or small molecules achieves clinical benefits in diverse solid malignancies. Nonetheless, therapeutic effects are usually not sustained, and most patients eventually succumb to progressive disease, indicating that antiangiogenic strategies require additional optimization. Vaccination with lethally irradiated, autologous tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF) and antibody blockade of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) trigger a tumor vasculopathy in some long-term responding subjects. These reactions are characterized by disrupted tumor blood vessels in association with lymphocyte and granulocyte infiltrates and zonal areas of ischemic tumor necrosis. However, the mechanisms underlying this immune-mediated destruction of the tumor vasculature remain to be clarified. Here, we show that GM-CSF-secreting tumor cell vaccines and CTLA-4 blockade elicit a functionally important humoral reaction against multiple angiogenic cytokines. Antibodies to angiopoietin-1 and angiopoietin-2 block Tie-2 binding, downstream signaling, endothelial cell tube formation, and macrophage chemotaxis. Antibodies to macrophage inhibitory factor (MIF) attenuate macrophage Tie-2 expression and matrix metalloproteinase-9 (MMP-9) production. Together, these results delineate an immunotherapy-induced host response that broadly targets the angiogenic network in the tumor microenvironment.
authors.affiliation: Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schoenfeld
authors.forename: Masahisa
authors.initials: M
authors.lastname: Jinushi
authors.forename: Yukoh
authors.initials: Y
authors.lastname: Nakazaki
authors.forename: Daniel
authors.initials: D
authors.lastname: Wiener
authors.forename: Joosang
authors.initials: J
authors.lastname: Park
authors.forename: Robert
authors.initials: R
authors.lastname: Soiffer
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Martin
authors.initials: M
authors.lastname: Mihm
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
mesh_terms: D042683:Angiopoietin-1 / Q000276:immunology; D042702:Angiopoietin-2 / Q000276:immunology; D000818:Animals; D000912:Antibodies, Neoplasm / Q000096:biosynthesis* / Q000276:immunology; D000917:Antibody Formation; D015703:Antigens, CD / Q000276:immunology; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D015723:Gene Library; D006801:Humans; D056724:Immunity, Humoral; D016233:Immunotherapy, Active / Q000379:methods*; D008545:Melanoma / Q000276:immunology / Q000628:therapy; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000098:blood supply* / Q000276:immunology / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000628:therapy; D042787:Receptor, TIE-2 / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000912:Antibodies, Neoplasm; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; C556707:Ctla4 protein, mouse; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2