1011. Tumor Specific Oncolytic Adenovirus Vector VRX-011 Which Overproduces ADP and Has the E4 Promoter Replaced by the hTERT Promoter

Abstract

We have previously evaluated the conditionally replicating adenovirus (Ad) vector named KD3 for possible use in anti-cancer therapy. KD3 markedly overexpresses ADP, an Ad nuclear membrane glycoprotein required at late stages of infection for efficient cell lysis and release of Ad from cells. KD3 also has two E1A mutations that reduce its replication in primary cells but allow efficient replication in cancer cells. We have also reported on a replication-competent vector named VRX-007 which overexpresses ADP and has wild type E1A. VRX-007 showed remarkable early cytopathic effects, early cell lysis, large plaques, increased cell to cell dissemination in cultured cells, enhanced cytolysis of cultured cancer cells, and efficient suppression of tumor growth in animal models. In this report we describe the vector VRX-011, which is similar to VRX-007 except that the Ad E4 promoter has been replaced by the promoter for human telomerase (hTERT). Telomerase is an enzyme involved in the maintenance of chromosomal termini known as telomeres. About 90% of cancer cells have elevated levels of telomerase activity, whereas telomerase activity is not detected in normal somatic cells. Since E4 proteins are required for Ad replication, VRX-011 is expected to replicate in most cancer cell types but not (well) in non-cancerous cells. VRX-011 replicated as well as Ad5 in the majority of cancer cell lines tested and was growth restricted in primary cells. Ad late protein expression was at normal levels in A549 human lung cancer cells but was markedly reduced in primary cells. Intratumor administration of VRX-011 effectively suppressed Hep3B liver carcinoma xenograft growth in nude mice. Systemic administration of VRX-011 by tail vein injection also efficiently suppressed Hep3B xenograft growth in nude mice. Also, intravenous administration of VRX-011 significantly reduced the number and size of A549 cancer cell metastases in nude mice lungs. Single tail vein administration of different PFU doses of VRX-011 in C57B/6 mice showed no toxicity as indicated by liver enzyme levels and animal weights. These in vitro and in vivo data show that VRX-011 has enhanced specific oncolytic efficacy and restriction in primary cells. VRX-011 may be useful in treating different types of human cancer.