Oncolytic adenoviruses in combination treatments for cancer: Examining the roles of cyclophosphamide and radiation in enhancing antitumor efficacy and viral replication and biodistribution in the Syrian hamster

Oncolytic virotherapy is a promising field of cancer treatment in which replication-competent viruses, including adenoviruses (Ads), can infect and lyse tumor cells. Syrian hamsters, unlike mice, are semi-permissive to human adenovirus type 5 (Ad5) and provide a useful immunocompetent model for evaluating anti-tumor efficacy, toxicity, and biodistribution of Ad vectors. VRX-007 (an Ad5-based vector) can replicate in subcutaneous Syrian hamster renal cancer (HaK) tumors and induce tumor suppression when injected intratumorally. Multimodality treatment is a standard practice in the treatment of cancer patients, and we have combined cyclophosphamide (CP) and radiotherapy with VRX-007 to treat HaK tumors.;We have previously reported that CP induces immunosuppression and enhances the antitumor efficacy of VRX-007. We recently discovered that short-term CP treatment, given for only one week before infection, has a similar effect on tumor growth as does long-term continuous treatment. Prolonged VRX-007 replication was only demonstrated in tumors from animals receiving long-term CP treatment. Thus, neither long-term immunosuppression via CP nor long-term viral replication is required for enhanced antitumor efficacy. Furthermore, the efficacy did not differ whether CP treatment was dosed before or after infection, suggesting that CP and VRX-007 produce independent antitumor activities.;We added tumor-specific radiation as a third treatment modality to vector and CP therapies. Radiation did not induce increased viral replication but did augment the suppression of tumor growth when combined with vector and/or CP. Treatment with radiation, enhanced antitumor efficacy regardless of whether it was dosed before or after infection. All three treatments combined to strongly inhibit tumor growth.;Furthermore, we evaluated the role of CP on viral replication in the livers of hamsters and mice. We showed that Ad5 can replicate in mice treated with CP. The drug even enhanced vector replication in immunodeficient mouse strains and in irradiated mice, which hints that CP-induced immunosuppression may not be the mechanism involved. CP has pleiotropic effects and likely affects cancer treatment through multiple actions.