title: The generation and analyses of a novel combination of recombinant adenovirus vaccines targeting three tumor antigens as an immunotherapeutic.
abstract: Phenotypic heterogeneity of human carcinoma lesions, including heterogeneity in expression of tumor-associated antigens (TAAs), is a well-established phenomenon. Carcinoembryonic antigen (CEA), MUC1, and brachyury are diverse TAAs, each of which is expressed on a wide range of human tumors. We have previously reported on a novel adenovirus serotype 5 (Ad5) vector gene delivery platform (Ad5 [E1-, E2b-]) in which regions of the early 1 (E1), early 2 (E2b), and early 3 (E3) genes have been deleted. The unique deletions in this platform result in a dramatic decrease in late gene expression, leading to a marked reduction in host immune response to the vector. Ad5 [E1-, E2b-]-CEA vaccine (ETBX-011) has been employed in clinical studies as an active vaccine to induce immune responses to CEA in metastatic colorectal cancer patients. We report here the development of novel recombinant Ad5 [E1-, E2b-]-brachyury and-MUC1 vaccine constructs, each capable of activating antigen-specific human T cells in vitro and inducing antigen-specific CD4+ and CD8+ T cells in vaccinated mice. We also describe the use of a combination of the three vaccines (designated Tri-Ad5) of Ad5 [E1-, E2b-]-CEA, Ad5 [E1-, E2b-]-brachyury and Ad5 [E1-, E2b-]-MUC1, and demonstrate that there is minimal to no "antigenic competition" in in vitro studies of human dendritic cells, or in murine vaccination studies. The studies reported herein support the rationale for the application of Tri-Ad5 as a therapeutic modality to induce immune responses to a diverse range of human TAAs for potential clinical studies.
authors.affiliation: Etubics Corporation, Seattle, WA, USA.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Gabitzsch
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Kwong Yok
authors.initials: KY
authors.lastname: Tsang
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Palena
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Justin M
authors.initials: JM
authors.lastname: David
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Fantini
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Kwilas
authors.affiliation: Etubics Corporation, Seattle, WA, USA.
authors.forename: Adrian E
authors.initials: AE
authors.lastname: Rice
authors.affiliation: Etubics Corporation, Seattle, WA, USA.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Latchman
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Hodge
authors.affiliation: Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Gulley
authors.affiliation: Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ravi A
authors.initials: RA
authors.lastname: Madan
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Heery
authors.affiliation: Etubics Corporation, Seattle, WA, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Balint
authors.affiliation: Etubics Corporation, Seattle, WA, USA.
authors.forename: Frank R
authors.initials: FR
authors.lastname: Jones
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D017498:Adenovirus E1 Proteins / Q000235:genetics / Q000276:immunology; D017502:Adenovirus E2 Proteins / Q000235:genetics / Q000276:immunology; D062705:Adenovirus Vaccines / Q000627:therapeutic use*; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007114:Immunization; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D017498:Adenovirus E1 Proteins; D017502:Adenovirus E2 Proteins; D062705:Adenovirus Vaccines; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D007371:Interferon-gamma
keywords: adenovirus vaccines; brachyury; cancer vaccines; immunotherapy; tumor antigens