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Published on: January 7, 2019
OvAd1, a Novel, Potent, and Selective Chimeric Oncolytic Virus Developed for Ovarian Cancer by 3D-Directed Evolution
Irene Kuhn1, Maxine Bauzon1, Nicola Green2
1Department of Biological Research, Bayer Pharmaceuticals, 455 Mission Bay Boulevard South, Suite 493, San Francisco, CA 94158, USA.
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.
Insights
New oncolytic viruses show promise for treating chemotherapy-resistant ovarian cancer. A 3D Matrigel culture method improved virus safety and efficacy, leading to potent cancer cell targeting with reduced normal cell impact.
Area of Science:
- Oncology
- Virology
- Biotechnology
Background:
- Ovarian cancer remains a significant health challenge, with chemotherapy resistance necessitating novel therapeutic strategies.
- Current treatments often lack specificity and can lead to severe side effects.
Purpose of the Study:
- To develop novel oncolytic viruses for ovarian cancer treatment.
- To evaluate the efficacy of a 3D Matrigel culture-based directed evolution method for generating oncolytic virotherapies.
Main Methods:
- Directed evolution of oncolytic viruses using 3D Matrigel cultures (OvAd1) and traditional monolayer cultures (OvAd2).
- In vitro testing against platinum-resistant ovarian cancer cell lines and normal cells.
- In vivo evaluation in an ovarian carcinomatosis model.
Main Results:
- Both OvAd1 and OvAd2 demonstrated potent activity against ovarian cancer cells with a ~200-fold therapeutic window.
- Matrigel-based evolution yielded OvAd1, which showed superior tumor suppression in vivo and enhanced attenuation on normal cells compared to OvAd2.
- Neither virus induced peritoneal adhesions, unlike Ad5-based therapies.
Conclusions:
- 3D Matrigel culture enhances directed evolution of oncolytic viruses for improved safety and efficacy in ovarian cancer.
- OvAd1 and OvAd2 represent promising candidates for treating aggressive and resistant ovarian cancers.
- These novel oncolytic viruses offer a potential alternative to existing therapies with a favorable safety profile.
