title: Enhancement of glioma-specific immunity in mice by "NOBEL", an insulin-like growth factor 1 receptor antisense oligodeoxynucleotide.
abstract: Autologous glioblastoma multiforme tumor cells treated with an antisense oligodeoxynucleotide (AS-ODN) targeting insulin-like growth factor receptor-1 (IGF-1R) are the basis of a vaccine with therapeutic effects on tumor recurrence in a pilot clinical trial. As a preface to continued clinical investigation of this vaccination strategy, we have studied the contribution of an optimized IGF-1R AS-ODN, designated "NOBEL", to the induction of immunity to mouse GL261 glioma cells. The impact of NOBEL on mechanisms contributing to the development of GL261 immunity was first examined in the periphery. GL261 cells are naturally immunogenic when implanted into the flanks of congenic C57BL/6 mice, immunizing rather than forming tumors in around 50 % of these animals but causing tumors in the majority of mice lacking T and B lymphocytes. Overnight treatment with NOBEL in vitro reduces IGF-1R expression by GL261 cells but has minimal effect on cell viability and does not reduce the capacity of the cells to form tumors upon implantation. In contrast, tumors are extremely rare when GL261 cells are mixed with NOBEL at inoculation into the flanks of C57BL/6, and the recipient mice become immune to subcutaneous and intracranial challenge with untreated GL261. Adaptive immune mechanisms contribute to this effect, as immunocompromised mice fail to either fully control tumor formation or develop immunity following flank administration of the GL261/NOBEL mix. NOBEL's structure has known immunostimulatory motifs that likely contribute to the immunogenicity of the mix, but its specificity for IGF-1R mRNA is also important as a similarly structured sense molecule is not effective.
authors.affiliation: Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Morin-Brureau
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Hooper
authors.forename: Michael
authors.initials: M
authors.lastname: Prosniak
authors.forename: Sami
authors.initials: S
authors.lastname: Sauma
authors.forename: Larry A
authors.initials: LA
authors.lastname: Harshyne
authors.forename: David W
authors.initials: DW
authors.lastname: Andrews
authors.forename: D Craig
authors.initials: DC
authors.lastname: Hooper
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005910:Glioma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D007111:Immunity, Cellular / Q000276:immunology*; D007167:Immunotherapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D001613:beta 2-Microglobulin / Q000502:physiology
chemical_list: D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D001613:beta 2-Microglobulin; D017526:Receptor, IGF Type 1