Ad5-triCoV/Mac(CIHR)

Ad5/35 chimeric oncolytic viruses (OVs) have earlier been shown to increase the level of vector transduction, intratumoral virus spread and survival in a number of xenograft models when compared with Ad5-based viruses. Because radiation and chemotherapy are the current standards of care for most cancer indications, Ad5/35 OVs have been tested here in combination with either radiation or chemotherapy in a head and neck cancer (HNC) xenograft model to determine whether such combination therapies enhance the potency of the virus, thereby leading to a greater therapeutic effect. In mice treated with either Ad5 OV (OV-5) or Ad5/35 chimeric OV (OV-5T35H), there was a delay in tumor progression compared with animals treated with phosphate-buffered saline (PBS) alone. When Ad5/35 chimeric OV and radiation were used in combination, there was a further delay in tumor progression, which resulted in a significant increase in the mean survival time of tumor-bearing mice compared with Ad5/35 or Ad5 OV monotherapy or to the combination of Ad5 OV with radiation, which was significantly less potent (P<0.0001) compared with the Ad5/35 OV plus radiation combination. Similarly, a combination of Ad5/35 chimeric OV with cisplatin significantly delayed tumor progression compared with Ad5/35 OV or Ad5 OV virus alone or with the combination of Ad5 virus with cisplatin (P<0.01). In summary, the combination of the potent Ad5/35 chimeric OV with either radiation or chemotherapy leads to significantly increased survival of mice bearing highly aggressive tumors, and may therefore offer an effective treatment strategy for patients with difficult to treat HNC.

Purpose: Evaluate the codelivery of hyaluronidase enzyme with oncolytic adenoviruses to determine whether it improves the spread of the virus throughout tumors, thereby leading to a greater overall antitumor efficacy in tumor models.Experimental Design: The optimal dose of hyaluronidase that provided best transduction efficiency and spread of a green fluorescent protein (GFP)-expressing adenovirus within tumors was combined with oncolytic viruses in tumor models to determine whether the combination treatment results in an improvement of antitumor efficacy.Results: In mice injected with the adenovirus Ad5/35GFP and an optimal dose of hyaluronidase (50 U), a significant increase in the number of GFP-expressing cells was observed when compared with animals injected with virus only (P &lt; 0.0001). When the oncolytic adenoviruses Ad5OV or Ad5/35 OV (OV-5 or OV5T35H) were codelivered with 50 U of hyaluronidase, a significant delay in tumor progression was observed, which translated into a significant increase in the mean survival time of tumor-bearing mice compared with either of the monotherapy-treated groups (P &lt; 0.0001). Furthermore, the mice that received the combination of Ad5/35 OV and hyaluronidase showed the best antitumor efficacy. Importantly, the combination treatment did not increase the metastatic potential of the tumors. Lastly, the increase in virus potency observed in animals injected with both enzyme and virus correlated with enhanced virus spread throughout tumors.Conclusion: Antitumor activity and overall survival of mice bearing highly aggressive tumors are significantly improved by codelivery of oncolytic adenoviruses and hyaluronidase when compared with either of the monotherapy-treated groups, and it may prove to be a potent and novel approach to treating patients with cancer.