647. Evaluation of Dose, Scheduling, Combination with Chemotherapy and Specificity of Ad5/3 Fiber-Chimeric Oncolytic Adenoviruses for Treatment of Ovarian Cancer
Authors: Mari Raki, Lotta Kangasniemi, Anna Kanerva, Gerd Bauerschmitz, Helena Isoniemi, Krister Hockerstedt, Akseli Hemminki
Journal: Molecular Therapy (2006)

Conditionally replicating adenoviruses (CRAds) represent a potent approach for treatment of neoplastic diseases. Replication of CRAds can be restricted to cancer cells in two different ways: limit the expression of viral E1A to tumor tissues with tumor-specific promoters or engineer deletions in genes critical for viral replication in normal cells but not in tumor cells. Gene therapy applications are usually based on Ad serotype 5, which binds to the coxsackie- adenovirus receptor (CAR). However, expression of CAR is frequently dysregulated in many types of advanced cancers. Substituting the knob domain of Ad5 with the corresponding domain of serotype 3 allows CAR-independent binding and entry through the Ad3 receptor, which is expressed to high degree on ovarian cancer cells. Ad5/3-Δ24 is a serotype 3 receptor targeted CRAd which contains a 24 bp deletion in E1A, rendering it unable to bind the Rb protein for induction of viral replication in non-cycling normal cells. This results in selective replication in cells deficient in the Rb/p16 pathway, including most cancer cells. Utilizing dose de-escalation in an orthotopic murine model of peritoneally disseminated ovarian cancer, we found that even a single viral dose of 100 VP increased the survival of mice significantly compared to untreated animals. Also, treatment with a single viral injection did not differ significantly from weekly injections. As predicted by classic virological postulates, amplification of Ad5/3-Δ24 seems to proceed on a logarithmic scale, resulting in lack of a clear dose response. A powerful approach for increasing antitumor efficacy is utilization of CRAds in combination with conventional therapies. We have previously demonstrated that combination of Ad5/3-Δ24 and deoxycytidine analogue gemcitabine delivers a synergistic effect to ovarian cancer cells both in vitro and in vivo. However, enhanced efficacy was sometimes associated with increased liver toxicity. To investigate the generalizability of these findings, we evaluated the combination of Ad5/3-Δ24 and gemcitabine in another aggressive model of peritoneally disseminated ovarian cancer. The combination resulted in significant increase in survival, and hepatic toxicity was circumvented by using lower doses of gemcitabine. Further, we combined Ad5/3-Δ24 with epirubicin, a potent anthracyclin, for increased efficacy without evidence of toxicity. The selectivity of deletion type CRAds might be improved by using tissue-specific promoters. Ad5/3-Cox2L-Δ24 is a serotype 3 targeted CRAd that contains a cyclooxygenase-2 (cox-2) promoter controlling expression of E1A. Cox-2 is highly expressed in many epithelial cancers including ovarian cancer. We compared Ad5/3-Δ24 to Ad5/3-Cox2L-Δ24 in vivo with regard to efficacy and toxicity. Further, we utilized human liver slices for analyzing the effect of the added promoter on safety.