The Enhanced Tumor Selectivity of an Oncolytic Vaccinia Lacking the Host Range and Antiapoptosis Genes SPI-1 and SPI-2

Abstract

The ability of cancer cells to evade apoptosis may permit survival of a recombinant vaccinia lacking antiapoptotic genes in cancer cells compared with normal cells. We have explored the deletion of two vaccinia virus host range/ antiapoptosis genes, SPI-1 and SPI-2, for their effects on the viral replication and their ability to induce cell death in infected normal and transformed cells in vitro. Indeed, in three paired normal and transformed cell types, the SPI-1 and SPI-2 gene-deleted virus (vSP) preferentially replicates in transformed cells or p53-null cells when compared with their normal counterparts. This selectivity may be derived from the fact that vSP-infected normal cells died faster than infected cancer cells. A fraction of infected cells died with evidence of necrosis as shown by both flow cytometry and detection of high-mobility group B1 protein released from necrotic cells into the culture supernatant. When administered to animals, vSP retains full ability to replicate in tumor tissues, whereas replication in normal tissues is greatly diminished. In a model of viral pathogenesis, mice treated with vSP survived substantially longer when compared with mice treated with the wild-type virus. The mutant virus vSP displayed significant antitumoral effects in an MC38 s.c. tumor model in both nude (P < 0.001) and immunocompetent mice (P < 0.05). We conclude that this recombinant vaccinia vSP shows promise for oncolytic virus therapy. Given its enhanced tumor selectivity, improved safety profile, and substantial oncolytic effects following systemic delivery in murine models, it should also serve as a useful vector for tumor-directed gene therapy. (Cancer Res 2005; 65(21): 9991-8)

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

“…However, the observation that the tumor microenvironment tends to be pro-oxidative 63 implies that a therapeutic approach using antioxidants to decrease ROS production would be favorable to stimulate antitumor immunity. Importantly, many anticancer agents, including chemotherapy, 30 radiation, 22 or oncolytic viruses, 9,64,65 have been shown to induce HMGB1 release from cancer cells, highlighting the significance of further addressing the mechanism of how these modalities affect the redox status of HMGB1.…”

“…113 Recent studies delineated that oncolytic viruses such as vaccinia, measles, HSV-2, and adenovirus cause the release of HMGB1. 64,65,114,115,116,117 Although HMGB1 interacts with viral components and may modulate viral replication, 117 the molecular mechanisms of how each oncolytic virus differentially produces these DAMPs remain largely elusive.…”

Oncolytic virotherapy for ovarian carcinomatosis using a replication-selective vaccinia virus armed with a yeast cytosine deaminase gene

“…After three freeze-thaw cycles, virus was quantified by plaque titering on CV-1 cells as described previously. 25,26 In vitro cytotoxicity assays The viability of cells infected with various amounts of vvDD or vvDD-CD alone or in combination with 5-FC was assessed using an MTS assay as per the manufacturer's protocol (Promega Corp, Madison, WI). Briefly, 5.0 Â 10 3 cells were plated in triplicate in 96-well flat bottom tissue culture plates (Costar, Corning, NY) overnight.…”

“…[22][23][24][25] We have shown that a number of tumorselective VV can inhibit cancer models after systemic delivery in both nude and immunocompetent mice. [25][26][27] Toxicity studies indicate that the highly tumor-selective vvDD is safe in nonhuman primates. 28 Most importantly, preliminary results from phase I/II clinical trials suggest that oncolytic VV are effective in human cancer patients.…”

Oncolytic vaccinia virus: a silver bullet?

“…There are now clinical trials ongoing, testing the expression of a cytokine and/or antigenic bacterial proteins. The remaining toxicity of TK-VV is also being reduced by the deletion of other viral genes [26,27]. In addition, other genes that can be inserted into VV and delivered to tumors, notably prodrugconverting enzymes, are also in development.…”