title: Sequential delivery of interferon-alpha gene and DCs to intracranial gliomas promotes an effective antitumor response.
abstract: Effective presentation of tumor antigens by dendritic cells (DCs) is considered to be essential for the induction of antitumor T-cell responses. Apoptotic and necrotic tumors have been noted to be a robust antigen source for DCs. Because glioma cells undergo apoptosis after transfection with the type I interferon (IFN) gene and type I IFNs promote the stimulatory activity of DCs, we hypothesized that transfection of glioma cells with type I IFN genes and provision of DCs would promote particularly effective antitumor activity by both facilitating apoptosis of glioma cells and the presentation of the glioma antigens, thereby inducing specific immune responses against glioma cells. We have previously reported the proof of this hypothesis in vitro and in a subcutaneous tumor model. Here we report an extension of this approach in intracranial (i.c.) gliomas using adenoviral IFN-alpha (Ad-IFN-alpha) vector. Mice bearing day-5 i.c. GL261 glioma received sequential intratumoral (i.t.) delivery of Ad-IFN-alpha and bone marrow-derived syngeneic DCs. This treatment prolonged survival in that nine of 17 animals survived long term (> 60 days versus 0 of 10 control animals). Specific CTL activity was demonstrated following this regimen in the cervical lymph nodes, and the therapeutic efficacy was dependent upon CD8+ cells. Furthermore, these animals were protected against subsequent re-challenge with GL261 gliomas. DCs injected i.t. survived in the tumor and migrated into cervical lymph node. In vitro migration assays revealed the ability of DCs to migrate toward the tumor, suggesting that i.t. injected DCs migrate through the glioma. Taken together, this combination of gene therapy and cellular immunotherapy may be an effective future strategy for treating human gliomas.
authors.affiliation: Department of Neurological Surgery, University of Pittsburgh School of Medicine, PA 15213-1863, USA.
authors.forename: T
authors.initials: T
authors.lastname: Tsugawa
authors.forename: N
authors.initials: N
authors.lastname: Kuwashima
authors.forename: H
authors.initials: H
authors.lastname: Sato
authors.forename: W K
authors.initials: WK
authors.lastname: Fellows-Mayle
authors.forename: J E
authors.initials: JE
authors.lastname: Dusak
authors.forename: K
authors.initials: K
authors.lastname: Okada
authors.forename: G D
authors.initials: GD
authors.lastname: Papworth
authors.forename: S C
authors.initials: SC
authors.lastname: Watkins
authors.forename: A
authors.initials: A
authors.lastname: Gambotto
authors.forename: J
authors.initials: J
authors.lastname: Yoshida
authors.forename: I F
authors.initials: IF
authors.lastname: Pollack
authors.forename: H
authors.initials: H
authors.lastname: Okada
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D017209:Apoptosis; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy*; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D005910:Glioma / Q000276:immunology / Q000628:therapy*; D016219:Immunotherapy, Adoptive / Q000379:methods*; D015552:Injections, Intralesional; D016898:Interferon-alpha / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014161:Transduction, Genetic / Q000379:methods
chemical_list: D000951:Antigens, Neoplasm; D016898:Interferon-alpha