Oncotarget

Research Papers:

Pseudotyped αvβ6 integrin-targeted adenovirus vectors for ovarian cancer therapies

Hanni Uusi-Kerttula _, James Davies, Lynda Coughlan, Sarah Hulin-Curtis, Rachel Jones, Louise Hanna, John D. Chester and Alan L. Parker

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Oncotarget. 2016; 7:27926-27937. https://doi.org/10.18632/oncotarget.8545

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Abstract

Hanni Uusi-Kerttula1, James Davies1, Lynda Coughlan2, Sarah Hulin-Curtis1, Rachel Jones3, Louise Hanna3, John D. Chester1,3, Alan L. Parker1

1Department of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK

2Nuffield Department of Medicine, The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK

3Velindre Cancer Centre, Cardiff CF14 2TL, UK

Correspondence to:

Alan L. Parker, e-mail: [email protected]

Keywords: adenovirus, re-targeting, neutralizing antibody, ovarian cancer, αvβ6 integrin

Received: February 05, 2016     Accepted: March 28, 2016     Published: April 1, 2016

ABSTRACT

Encouraging results from recent clinical trials are revitalizing the field of oncolytic virotherapies. Human adenovirus type 5 (HAdV-C5/Ad5) is a common vector for its ease of manipulation, high production titers and capacity to transduce multiple cell types. However, effective clinical applications are hindered by poor tumor-selectivity and vector neutralization. We generated Ad5/kn48 by pseudotyping Ad5 with the fiber knob domain from the less seroprevalent HAdV-D48 (Ad48). The vector was shown to utilize coxsackie and adenovirus receptor (CAR) but not CD46 for cell entry. A 20-amino acid peptide NAVPNLRGDLQVLAQKVART (A20) was inserted into the Ad5. Luc HI loop (Ad5.HI.A20) and Ad5/kn48 DG loop (Ad5/kn48.DG.A20) to target a prognostic cancer cell marker, αvβ6 integrin. Relative to the Ad5.Luc parent vector, Ad5.HI.A20, Ad5.KO1.HI.A20 (KO1, ablated CAR-binding) and Ad5/kn48.DG.A20 showed ~ 160-, 270- and 180-fold increased transduction in BT-20 breast carcinoma cells (αvβ6high). Primary human epithelial ovarian cancer (EOC) cultures derived from clinical ascites provided a useful ex vivo model for intraperitoneal virotherapy. Ad5.HI.A20, Ad5.KO1.HI.A20 and Ad5/kn48.DG.A20 transduction was ~ 70-, 60- and 16-fold increased relative to Ad5.Luc in EOC cells (αvβ6high), respectively. A20 vectors transduced EOC cells at up to ~ 950-fold higher efficiency in the presence of neutralizing ovarian ascites, as compared to Ad5.Luc. Efficient transduction and enhanced cancer-selectivity via a non-native αvβ6-mediated route was demonstrated, even in the presence of pre-existing anti-Ad5 immunity. Consequently, αvβ6-targeted Ad vectors may represent a promising platform for local intraperitoneal treatment of ovarian cancer metastases.


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