title: OvAd1, a Novel, Potent, and Selective Chimeric Oncolytic Virus Developed for Ovarian Cancer by 3D-Directed Evolution.
abstract: Effective therapeutics for ovarian cancer continue to be urgently needed, particularly for chemotherapy-resistant cases. Here we present both a 3D-Matrigel culture-based expansion of our directed evolution method for generation of oncolytic virotherapies and two promising ovarian-cancer targeted oncolytic viruses, OvAd1 and OvAd2. OvAd1 was developed using Matrigel cell cultures, whereas OvAd2 was developed in parallel using traditional monolayer tissue culture methods. Both viruses are potent against a panel of platinum-resistant ovarian cancer cell lines and are attenuated on normal cells in vitro, resulting in therapeutic windows of ∼200-fold. We observed two benefits of the use of Matrigel-based cultures for directed evolution of these oncolytics: (1) use of Matrigel generated a bioselected pool that was more strongly attenuated on normal cells while retaining its potency against ovarian cancer cells, and (2) in an ovarian carcinomatosis model, the Matrigel-derived virus OvAd1 suppressed all tumor growth while the non-Matrigel-derived virus was 50% effective. Neither virus stimulated formation of peritoneal adhesions as seen for Ad5-based therapies. Consequently, these viruses are novel candidates for development as new effective treatments for aggressive ovarian cancer.
authors.affiliation: Department of Biological Research, Bayer Pharmaceuticals, 455 Mission Bay Boulevard South, Suite 493, San Francisco, CA 94158, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Kuhn
authors.affiliation: Department of Biological Research, Bayer Pharmaceuticals, 455 Mission Bay Boulevard South, Suite 493, San Francisco, CA 94158, USA.
authors.forename: Maxine
authors.initials: M
authors.lastname: Bauzon
authors.affiliation: Department of Clinical Medicine, University of Oxford, Old Road Campus, OX3 7DQ, Oxford, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Green
authors.affiliation: Department of Oncology, University of Oxford, Old Road Campus, OX3 7DQ, Oxford, UK.
authors.forename: Len
authors.initials: L
authors.lastname: Seymour
authors.affiliation: Department of Oncology, University of Oxford, Old Road Campus, OX3 7DQ, Oxford, UK.
authors.forename: Kerry
authors.initials: K
authors.lastname: Fisher
authors.affiliation: Department of Biological Research, Bayer Pharmaceuticals, 455 Mission Bay Boulevard South, Suite 493, San Francisco, CA 94158, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Hermiston
keywords: 3D cell culture; Matrigel; adenovirus; directed evolution; oncolytic; ovarian cancer; replicating; virotherapy