title: A Genetically Modified Adenoviral Vector with a Phage Display-Derived Peptide Incorporated into Fiber Fibritin Chimera Prolongs Survival in Experimental Glioma.
abstract: The dismal clinical context of advanced-grade glioma demands the development of novel therapeutic strategies with direct patient impact. Adenovirus-mediated virotherapy represents a potentially effective approach for glioma therapy. In this research, we generated a novel glioma-specific adenovirus by instituting more advanced genetic modifications that can maximize the efficiency and safety of therapeutic adenoviral vectors. In this regard, a glioma-specific targeted fiber was developed through the incorporation of previously published glioma-specific, phage-panned peptide (VWT peptide) on a fiber fibritin-based chimeric fiber, designated as "GliomaFF." We showed that the entry of this virus was highly restricted to glioma cells, supporting the specificity imparted by the phage-panned peptide. In addition, the stability of the targeting moiety presented by fiber fibritin structure permitted greatly enhanced infectivity. Furthermore, the replication of this virus was restricted in glioma cells by controlling expression of the E1 gene under the activity of the tumor-specific survivin promoter. Using this approach, we were able to explore the combinatorial efficacy of various adenoviral modifications that could amplify the specificity, infectivity, and exclusive replication of this therapeutic adenovirus in glioma. Finally, virotherapy with this modified virus resulted in up to 70% extended survival in an in vivo murine glioma model. These data demonstrate that this novel adenoviral vector is a safe and efficient treatment for this difficult malignancy.
authors.affiliation: 1 Brain Tumor Center, University of Chicago Pritzker School of Medicine , Chicago, Illinois.
authors.forename: Julius W
authors.initials: JW
authors.lastname: Kim
authors.affiliation: 1 Brain Tumor Center, University of Chicago Pritzker School of Medicine , Chicago, Illinois.
authors.forename: J Robert
authors.initials: JR
authors.lastname: Kane
authors.affiliation: 1 Brain Tumor Center, University of Chicago Pritzker School of Medicine , Chicago, Illinois.
authors.forename: Jacob S
authors.initials: JS
authors.lastname: Young
authors.affiliation: 1 Brain Tumor Center, University of Chicago Pritzker School of Medicine , Chicago, Illinois.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Chang
authors.affiliation: 1 Brain Tumor Center, University of Chicago Pritzker School of Medicine , Chicago, Illinois.
authors.forename: Deepak
authors.initials: D
authors.lastname: Kanojia
authors.affiliation: 1 Brain Tumor Center, University of Chicago Pritzker School of Medicine , Chicago, Illinois.
authors.forename: Ramin A
authors.initials: RA
authors.lastname: Morshed
authors.affiliation: 1 Brain Tumor Center, University of Chicago Pritzker School of Medicine , Chicago, Illinois.
authors.forename: Jason
authors.initials: J
authors.lastname: Miska
authors.affiliation: 1 Brain Tumor Center, University of Chicago Pritzker School of Medicine , Chicago, Illinois.
authors.forename: Atique U
authors.initials: AU
authors.lastname: Ahmed
authors.affiliation: 1 Brain Tumor Center, University of Chicago Pritzker School of Medicine , Chicago, Illinois.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Balyasnikova
authors.affiliation: 1 Brain Tumor Center, University of Chicago Pritzker School of Medicine , Chicago, Illinois.
authors.forename: Yu
authors.initials: Y
authors.lastname: Han
authors.affiliation: 1 Brain Tumor Center, University of Chicago Pritzker School of Medicine , Chicago, Illinois.
authors.forename: Lingjiao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 2 Cancer Biology Division, Biologic Therapeutics Center, Department of Radiation Oncology, School of Medicine, Washington University in St. Louis , St. Louis, Missouri.
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.affiliation: 1 Brain Tumor Center, University of Chicago Pritzker School of Medicine , Chicago, Illinois.
authors.forename: Maciej S
authors.initials: MS
authors.lastname: Lesniak
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy*; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D005910:Glioma / Q000628:therapy*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics; D019151:Peptide Library; D014764:Viral Proteins / Q000235:genetics; D014779:Virus Replication
chemical_list: D019151:Peptide Library; D014764:Viral Proteins; C057839:fibritin protein, Enterobacteria phage T4