Vaccinia Virus-Mediated Expression of Transcription Factor Klf4 Enhances Oncolytic Virotherapy of Colorectal Cancer

Abstract

Colorectal cancer (CRC) detected at an early stage has a good prognosis, however, recurrence of the disease is prevalent and late stage CRC (stage IIIC and IV) has observed 5-year survival rates of 28% and 6%, respectively. Oncolytic virotherapy has been explored as a potential treatment modality in cancer therapy for its safety and tumor specificity. We recently reported that oncolytic vaccinia virus GLV-1h68 efficiently infected, replicated in, and lysed different colorectal cancer cell lines derived from patients at different stages of the disease in culture and mouse xenograft models. However, the cytotoxicity of GLV-1h68 was cell linedependent and, in particular, xenograft tumors of the colorectal cancer cell line HT-29 did not respond favorably to oncolytic treatment with GLV-1h68. Here we report on the generation of recombinant vaccinia viruses expressing the colorectal tumor suppressor Klf4. We show that a single injection of vaccinia virus expressing Klf4 led to significant tumor growth inhibition of HT-29 human colon cancer xenografts in comparison to treatment with GLV-1h68. Furthermore, virus-mediated expression of a membrane-permeable Klf4-TAT fusion protein, further improved the anti-tumoral effects. This is the first report demonstrating that arming oncolytic viruses with the colorectal tumor suppressor Klf4 led to improved therapy in a human colon cancer xenograft model.