Replication-competent retrovirus vector-mediated prodrug activator gene therapy in experimental models of human malignant mesothelioma

Abstract

Replication-competent retrovirus (RCR) vectors have been shown to achieve significantly enhanced tumor transduction efficiency and therapeutic efficacy in various cancer models. In the present study, we investigated RCR vector-mediated prodrug activator gene therapy for the treatment of malignant mesothelioma, a highly aggressive tumor with poor prognosis. RCR vector expressing the green fluorescent protein marker gene (RCR-GFP) successfully infected and efficiently replicated in human malignant mesothelioma cell lines, as compared to non-malignant mesothelial cells in vitro. In mice with pre-established subcutaneous tumor xenografts, RCR-GFP vector showed robust spread throughout entire tumor masses after intratumoral administration. Next, RCR-CD, expressing the yeast cytosine deaminase (CD) prodrug activator gene, showed efficient transmission of the prodrug activator gene associated with replicative spread of the virus, resulting in efficient killing of malignant mesothelioma cells in a prodrug 5-fluorocytosine (5FC)-dose dependent manner in vitro. After a single intratumoral injection of RCR-CD followed by intraperitoneal administration of 5FC, RCR vector-mediated prodrug activator gene therapy achieved significant inhibition of subcutaneous tumor growth, and significantly prolonged survival in the disseminated peritoneal model of malignant mesothelioma. These data indicate the potential utility of RCR vector-mediated prodrug activator gene therapy in the treatment of malignant mesothelioma.

Highly efficient tumor transduction and antitumor efficacy in experimental human malignant mesothelioma using replicating gibbon ape leukemia virus

“…Using RRVs expressing the yeast cytosine deaminase (CD) prodrug activator gene, we have demonstrated highly efficient killing of a wide variety of cancer cells both in vitro and in vivo upon administration of its prodrug, 5-fluorocytosine (5FC). [15][16][17][18][19] Based on these promising preclinical results, two clinical trials for RRV-mediated prodrug activator gene therapy in patients with recurrent malignant brain tumor have recently been started in the United States (http://www. clinicaltrials.gov NCT01470794, NCT01156584).…”

“…In experimental human malignant mesothelioma, after a single intratumoral injection of RRV delivering the CD prodrug activator gene into xenografted human mesothelioma, RRV-mediated prodrug activator gene therapy also achieved significant inhibition of subcutaneous tumor growth, and significantly prolonged survival in the disseminated peritoneal model of malignant mesothelioma. 19 In addition, we have recently developed another RRV, which is derived from the gibbon ape leukemia virus (GALV). 20 Although GALV and AMLV both belong to the gammaretrovirus genus, they have divergent host ranges and are not in the same interference class, 21,22 as these viruses employ different receptors to infect target cells.…”

Oncolytic viruses: From bench to bedside with a focus on safety

“…Oncolytic activity of RCR-MuLV-CD (Toca 511) has been evaluated in preclinical (animal) models for breast cancer, GBM and mesothelioma. [148][149][150] Toca 511 has a modified backbone and a codonoptimized and heat-stabilized CD gene and has been shown to be highly genomically stable while maintaining oncolytic efficacy upon passaging. 145,149 Toca 511 is being investigated in clinical trials in the United States in subjects with recurrent high-grade glioma.…”

Latest developments in our understanding of the pathogenesis of mesothelioma and the design of targeted therapies

“…A phase I trial with MV-NIS is currently ongoing [NCT01503177]. Also adenovirus [208], retrovirus [209], and herpes simplex virus [210] have been examined for the therapeutic effects in preclinical settings, and are progressing to early human experimentation [NCT01721018, NCT01212367].…”