TRAIL gene-armed oncolytic poxvirus and oxaliplatin can work synergistically against colorectal cancer

Abstract

Summary We have explored a unique combination therapy for metastatic colorectal cancer. This strategy combines a potent and new oncolytic poxvirus expressing a membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or TNFSF10) and oxaliplatin (Ox) chemotherapy. We hypothesized that TRAIL expression would increase the efficacy of the oncolytic poxvirus, and that the therapeutic efficacy would be further enhanced by combination with chemotherapy. The cytotoxicity to cancer cells by Ox, oncolytic VV and trail gene-armed VV alone or in combination was tested in vitro. The trail gene armed oncolytic VV expressed high levels of TRAIL in infected cancer cells and had greater potency as a cytotoxic agent compared to the parent VV. Ox alone exerted concentration-dependent cytotoxicity. In vitro, the combination of the two agents applied at suboptimal concentrations for individual therapy displayed synergy in inducing cancer cells into enhanced levels of apoptosis/necrosis. Western blot analyses confirmed the notion that TRAIL induced cancer cell death mainly through apoptosis, while Ox and vJS6 may induce cell death more through non-apoptotic death pathways. In two aggressive colorectal carcinomatosis models derived from human HCT116 and murine MC38 cells, the combination therapy displayed synergistic or additive antitumor activity and prolonged the survival of the tumor-bearing mice compared to either Ox chemotherapy or vvTRAIL-mediated oncolytic gene therapy alone. This combination strategy may provide a new avenue to treating peritoneal carcinomatosis and other types of metastases of colorectal cancer.

Oncolytic vaccinia virus synergizes with irinotecan in colorectal cancer

“…Analysis of virus–drug interactions using the Chou–Talalay method (Chou and Talalay, 1984) demonstrated that vvDD synergizes with OX and SN‐38 in a dose‐, cell line‐ and schedule‐dependent manner. In contrast to previous work that reported no synergy between a different oncolytic VV (vJS6) and OX in MC38 and DLD1 cells (Ziauddin et al., 2010), we observed synergistic interactions in all cell lines tested (at specific doses with different treatment schedules). Differences in the virus backbone (vJS6; contains a single attenuation deletion, tk‐ ) as well as the selected dose combinations and experimental design may account for the divergent findings.…”

“…As with the vast majority of cancer therapies, OVs are unlikely to be delivered alone but rather as part of a rationally designed, combination therapy regimen (Ottolino‐Perry et al., 2010). OVs have been combined with surgical resection (Acuna et al., 2014; Gholami et al., 2013; Nakano et al., 2005; Tai et al., 2013), radiation (Advani et al., 2012; Mansfield et al., 2013), and numerous chemotherapy drugs (Cherubini et al., 2011; Gutermann et al., 2006; Heinemann et al., 2011; Huang et al., 2011; Maitra et al., 2014; Takakura et al., 2010; Zaoui et al., 2012; Ziauddin et al., 2010) in preclinical models. Combination OV and chemotherapy studies have demonstrated that particular combinations can be highly synergistic in specific tumour models.…”

“…It has previously been shown that OX synergistically improves killing in CRC cells when combined with VV expressing tumour necrosis factor (TNF)‐related apoptosis inducing ligand (TRAIL) (Ziauddin et al., 2010). Combination therapy significantly increased induction of apoptosis and improved survival relative to monotherapy in models of disseminated CRC in a transgene‐dependent manner.…”

Tumor vascularization is critical for oncolytic vaccinia virus treatment of peritoneal carcinomatosis

“…vvDD has previously been reported to inhibit growth of subcutaneous colorectal tumors 6 as well as improve survival in both immunosuppressed and immunocompetent models of ovarian carcinomatosis. 7 In immunocompetent CRC PC models, combination therapy with VV expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and oxaliplatin improved survival over either agent alone 14 and delivery of low dose vvDD in preimmunized mice was improved when combined with immunosuppression and carrier cells. 15 In our study, we report the use of vvDD in two orthotopic models of colorectal PC and are the first to report improved survival in a syngeneic model following intraperitoneal (IP) virus delivery.…”

Current Good Manufacturing Practice Production of an Oncolytic Recombinant Vesicular Stomatitis Viral Vector for Cancer Treatment

“…Despite their efficacy in animal models, a major limitation to the successful use of oncolytic viruses to treat cancer in patients is their relatively poor replication efficiency and limitations in spreading within the solid tumor mass in vivo, which typically contains complex stromal structures interspersed with the tumor cells. To overcome these obstacles, more virulent oncolytic viruses that retain tumor specificity and/or oncolytic viruses molecularly engineered to express transgenes that exert bystander effects for enhanced tumor cell killing have been used (Hardcastle et al, 2007;Singleton et al, 2007;Thorne et al, 2007;Gainey et al, 2008;Kuhn et al, 2008;Raykov et al, 2008;Xie et al, 2009;Ziauddin et al, 2010). Another limitation is the neutralizing antiviral antibody responses that are elicited within several days in immune-competent hosts, which shortens the window of opportunity for intratumoral replication.…”