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Published on: March 22, 2011
Enhanced therapeutic efficacy for ovarian cancer with a serotype 3 receptor-targeted oncolytic adenovirus
Anna Kanerva1, Kurt R Zinn, Tandra R Chaudhuri
1Division of Human Gene Therapy, Department of Medicine, Department of Pathology, and Department of Surgery, Finland.
Abstract:
Oncolytic viruses that are replication competent in tumor but not in normal cells represent a novel approach for treating neoplastic diseases. However, the oncolytic potency of replicating agents is determined directly by their capability of infecting target cells. Most adenoviruses used for gene therapy or virotherapy have been based on serotype 5 (Ad5). Unfortunately, expression of the primary receptor for Ad5 (the coxsackie-adenovirus receptor, or CAR) is highly variable on ovarian and other cancer cells. By performing genetic fiber pseudotyping, we created Ad5/3-Delta24, a conditionally replicating adenovirus that does not bind CAR but facilitates entry into and killing of ovarian cancer cells. We show replication of Ad5/3-Delta24 and subsequent oncolysis of ovarian adenocarcinoma lines. Replication was also analyzed with quantitative PCR on three-dimensional primary tumor cell spheroids purified from patient samples. Moreover, in a therapeutic orthotopic model of peritoneal carcinomatosis, dramatically enhanced survival was noted. Finally, Ad5/3-Delta24 achieved a significant antitumor effect as assessed by noninvasive, in vivo bioluminescence imaging. Therefore, the preclinical therapeutic efficacy of Ad5/3-Delta24 is improved over the respective CAR- and integrin-binding controls. Taken together with promising biodistribution and toxicity data, this approach could translate into successful clinical interventions for ovarian cancer patients.
Insights
This study introduces Ad5/3-Delta24, a novel oncolytic virus effective against ovarian cancer. This engineered adenovirus overcomes CAR receptor variability, enhancing tumor cell infection and leading to significant antitumor effects in preclinical models.
Area of Science:
- Oncolytic virotherapy
- Cancer gene therapy
- Adenovirus engineering
Background:
- Replication-competent oncolytic viruses offer a novel cancer treatment strategy.
- Adenovirus serotype 5 (Ad5) efficacy is limited by variable coxsackie-adenovirus receptor (CAR) expression on cancer cells.
- Target cell infection is critical for oncolytic virus potency.
Purpose of the Study:
- To develop a novel oncolytic adenovirus (Ad5/3-Delta24) that bypasses CAR-dependent entry.
- To evaluate the efficacy of Ad5/3-Delta24 in ovarian cancer models.
- To assess the therapeutic potential of Ad5/3-Delta24 for ovarian cancer treatment.
Main Methods:
- Genetic fiber pseudotyping was used to create Ad5/3-Delta24, an adenovirus engineered to not bind CAR.
- Replication and oncolysis were assessed in ovarian adenocarcinoma cell lines and patient-derived tumor spheroids.
- Therapeutic efficacy was evaluated in an orthotopic model of peritoneal carcinomatosis using bioluminescence imaging.
Main Results:
- Ad5/3-Delta24 demonstrated replication and oncolysis in ovarian cancer cells and patient tumor spheroids.
- Significant survival enhancement was observed in a preclinical model of peritoneal carcinomatosis.
- Ad5/3-Delta24 showed improved antitumor effects compared to CAR- and integrin-binding controls.
Conclusions:
- Ad5/3-Delta24 exhibits enhanced preclinical therapeutic efficacy against ovarian cancer by overcoming CAR dependency.
- The engineered adenovirus shows promise for clinical translation in ovarian cancer patients.
- Promising biodistribution and toxicity data support further clinical investigation.
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