title: Delivery of dendritic cells engineered to secrete IFN-alpha into central nervous system tumors enhances the efficacy of peripheral tumor cell vaccines: dependence on apoptotic pathways.
abstract: We tested whether modulation of the CNS-tumor microenvironment by delivery of IFN-alpha-transduced dendritic cells (DCs: DC-IFN-alpha) would enhance the therapeutic efficacy of peripheral vaccinations with cytokine-gene transduced tumor cells. Mice bearing intracranial GL261 glioma or MCA205 sarcoma received peripheral immunizations with corresponding irradiated tumor cells engineered to express IL-4 or GM-CSFs, respectively, as well as intratumoral delivery of DC-IFN-alpha. This regimen prolonged survival of the animals and induced tumor-specific CTLs that expressed TRAIL, which in concert with perforin and Fas ligand (FasL) was involved in the tumor-specific CTL activity of these cells. The in vivo antitumor activity associated with this approach was abrogated by administration of neutralizing mAbs against TRAIL or FasL and was not observed in perforin-/-, IFN-gamma-/-, or FasL-/- mice. Transduction of the tumor cells with antiapoptotic protein cellular FLIP rendered the gene-modified cells resistant to TRAIL- or FasL-mediated apoptosis and to CTL killing activity in vitro. Furthermore, the combination therapeutic regimen was ineffective in an intracranial cellular FLIP-transduced MCA205 brain tumor model. These results suggest that the combination of intratumoral delivery of DC-IFN-alpha and peripheral immunization with cytokine-gene transduced tumor cells may be an effective therapy for brain tumors that are sensitive to apoptotic signaling pathways.
authors.affiliation: Department of Neurological Surgery, University of Pittsburgh School of Medicine, PA 15213, USA.
authors.forename: Naruo
authors.initials: N
authors.lastname: Kuwashima
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Nishimura
authors.forename: Junichi
authors.initials: J
authors.lastname: Eguchi
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Sato
authors.forename: Manabu
authors.initials: M
authors.lastname: Hatano
authors.forename: Takahiko
authors.initials: T
authors.lastname: Tsugawa
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Sakaida
authors.forename: Jill E
authors.initials: JE
authors.lastname: Dusak
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Fellows-Mayle
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Papworth
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: Andrea
authors.initials: A
authors.lastname: Gambotto
authors.forename: Ian F
authors.initials: IF
authors.lastname: Pollack
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Storkus
authors.forename: Hideho
authors.initials: H
authors.lastname: Okada
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000235:genetics; D019264:Adoptive Transfer; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis / Q000276:immunology*; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis / Q000502:physiology / Q000627:therapeutic use; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation*; D005910:Glioma / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D015552:Injections, Intralesional; D007276:Injections, Intraventricular; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology*; D014161:Transduction, Genetic
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D016207:Cytokines; D016898:Interferon-alpha