642. Toxicological Findings with Oncolytic Adenovirus Vector VRX-007, Wild-Type Ad5, and a Replication-Defective Adenovirus Vector in Syrian Hamsters and C57BL/6 Mice
Authors: Karoly Toth, Jacqueline F. Spencer, Drew L. Lichtenstein, Ann E. Tollefson, Debabrata Patra, Jennifer M. Meyer, Elena Shashkova, Mohan Kuppuswamy, Konstantin Doronin, Debanjan Dhar, Maria A. Thomas, Louis A. Zumstein, William S.M. Wold
Journal: Molecular Therapy (2006)

We have developed VRX-007, a fully replication-competent (RC) oncolytic adenovirus (Ad) vector that has a faster replication cycle and is more cytolytic than wild-type Ad5 due to overexpression of the E3 11.6K Adenovirus Death Protein (ADP). VRX-007 is very efficacious against various human cancer cell lines and against tumors in the nude mouse, cotton rat, and Syrian hamster. Tissues of the last two animals are permissive for human Ad replication, and these animals have an intact immune system. Toxicology studies were performed in C57BL/6 mice and Syrian hamsters in order to establish the safety profile of VRX-007 in comparison to Ad5 and a replication-defective (RD) Ad vector. Mice have been traditionally used for toxicology studies with Ad vectors. However, as human Ads replicate very poorly in mice, this system is inadequate to model all effects of oncolytic Ad vectors in a human host. We developed the hamster as a new animal model for toxicology studies with RC Ad vectors, and established that Ad5 and VRX-007 replicate in the liver, lung, and some other tissues of hamsters. VRX-007 was injected intravenously at 1.5E11, 3E10, and 3E9 vp/kg into mice and at 1.9E12, 3E10, and 3E9 vp/kg into hamsters. Ad5 and the Ad RD vector were given at the high dose. Animals were sacrificed on days 2, 7, and 28 for gross and clinical pathology and histopathology observations. At the high-dose of VRX-007 and Ad5, mild to marked toxicity was observed in the liver as indicated by liver lesions and transaminitis. Minimal to moderate lesions were seen in some other organs (e.g. salivary gland, bone marrow). The side effect profiles in the Ad5 group were similar. One high-dose VRX-007- and one Ad5-injected hamster died of treatment-related causes. In the mid-dose group, minimal toxicity was found; this dose level was designated the No Observable Adverse Effect Level (NOAEL) in hamsters; this dose is equivalent to the maximum human dose anticipated in the clinic. No toxicity was seen in the low-dose VRX-007-treated animals. The Ad RD group displayed less toxicity than the Ad5 or VRX-007 groups. With mice, minimal to mild liver toxicity was seen in animals in the high-dose VRX-007, Ad5, and the RD vector groups. Other organs were largely unaffected. In contrast to hamsters, the severity of pathology in the high-dose VRX-007, Ad5, and RD vector groups was comparable, underscoring the difference in the replication of human Ads in the two species. In summary, the hamster is an excellent permissive immunocompetent model with which to estimate the toxicity of RC Ad vectors. We further conclude that VRX-007 retained the generally innocuous characteristics of its parental virus, Ad5, which does not cause clinically significant infections in immunocompetent adults. Based upon these results, we believe that VRX-007 warrants development as a novel anti-cancer agent. A portion of this research was funded by a biotechnology company named VirRx, Inc. KT, AET, KD, and WSMW have equity in VirRx.