title: Potent induction of B- and T-cell immunity against human carcinoembryonic antigen-expressing tumors in human carcinoembryonic antigen transgenic mice mediated by direct lentivector injection.
abstract: The applicability of immunotherapy would be dramatically broadened to a greater number of recipients if direct "off-the-shelf" products could be engineered to engender functionally potent immune responses against true "self"-tumor antigens. This would obviate the need for ex vivo culture of dendritic cells or T cells on a patient-by-patient basis, for example. The carcinoembryonic antigen (CEA) is a glycoprotein expressed in normal gut epithelium that is up-regulated in the majority of colon cancers, non-small cell lung cancers, and half of all breast cancers. Such properties make CEA an excellent and important target for cancer immunotherapy. In this study, we show stabilization of 14-day established s.c. mGC4CEA tumors in human CEA (huCEA) transgenic mice following two direct low-dose injections of 0.15x10(6) transducing units of a lentiviral vector (LV) that directs expression of huCEA (LV-huCEA). This stabilization result was reproducible and detailed analyses including antibody assays, multiplex cytokine analyses on unstimulated splenocytes, lymph node cell characterizations, tetramer staining, and immunofluorescence staining of tumor sections showed that this outcome correlated with both a cellular and humoral immune response. Similar tumor outcomes were not seen when mice were vaccinated with a control LV that engineered expression of enGFP only. The long-term potency of this vaccination strategy was also studied and revealed the requirement for maintenance of tumor antigen-specific immunity for efficient tumor control. These data support the use of direct injections of low doses of LV-huCEA for enhancement of tumor immunotherapy directed against CEA.
authors.affiliation: Ontario Cancer Institute, University Health Network, Department of Medical Biophysics, University of Toronto, 67 College Street, Toronto, Ontario, Canada M5G 2M1.
authors.forename: Severine
authors.initials: S
authors.lastname: Loisel-Meyer
authors.forename: Tania
authors.initials: T
authors.lastname: Felizardo
authors.forename: Jacopo
authors.initials: J
authors.lastname: Mariotti
authors.forename: Miriam E
authors.initials: ME
authors.lastname: Mossoba
authors.forename: Jason E
authors.initials: JE
authors.lastname: Foley
authors.forename: Robert
authors.initials: R
authors.lastname: Kammerer
authors.forename: Nobuo
authors.initials: N
authors.lastname: Mizue
authors.forename: Robert
authors.initials: R
authors.lastname: Keefe
authors.forename: J Andrea
authors.initials: JA
authors.lastname: McCart
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Zimmermann
authors.forename: Boro
authors.initials: B
authors.lastname: Dropulic
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Fowler
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Medin
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000235:genetics* / Q000276:immunology*; D002478:Cells, Cultured; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics*; D007167:Immunotherapy / Q000379:methods*; D007267:Injections; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology*; D047368:Tumor Burden
chemical_list: D002272:Carcinoembryonic Antigen