In vitro and in vivo activities of an oncolytic adenoviral vector designed to express GM-CSF.
Oncolytic adenoviruses are being tested as biological cancer therapeutics. Ar6pAE2fF (E2F vector) contains the E2F-1 promoter to regulate the expression of the E1a gene in cells with a disregulated retinoblastoma pathway. Ar6pAE2fmGmF (E2F-GM vector) includes the murine granulocyte-macrophage colony-stimulating factor (GM-CSF) transgene to enhance anti-tumor activity. Both vectors selectively killed human tumor cells in vitro. The E2F-GM vector expressed biologically active murine GM-CSF in vitro and GM-CSF was detected for several days in serum and tumor extracts following injections of established human xenograft tumors. In vivo, both vectors showed significant dose-dependent anti-tumor responses. The E2F-GM vector elicited greater efficacy compared to the E2F vector, demonstrating that GM-CSF enhanced the anti-tumor activity, even in immunodeficient nude mice. Histological analysis showed that both vectors induced necrosis and mononuclear cell infiltration, but only the E2F-GM vector resulted in eosinophil infiltration. Vector replication in vivo was demonstrated. The data showed that intratumoral injection of a GM-CSF-armed oncolytic vector induced potent anti-tumor responses in xenograft tumor models, likely as the result of both oncolytic vector activity and the induction of GM-CSF-mediated inflammation and innate immunity.
Bristol
J Andrew
JA
Oncology Unit, Genetic Therapy, Inc., A Novartis Company, 9 West Watkins Mill Road, Gaithersburg, Maryland 20878, USA.
Zhu
Mingzhu
M
Ji
Hong
H
Mina
Mervat
M
Xie
Yuefeng
Y
Clarke
Lori
L
Forry-Schaudies
Suzanne
S
Ennist
David L
DL
D000256:Adenoviridae / Q000502:physiology*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000628:therapy / Q000821:virology*; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000235:genetics / Q000628:therapy / Q000821:virology*; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics*; D014407:Tumor Cells, Cultured; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; D014157:Transcription Factors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor