Combination of Paclitaxel and MG1 Oncolytic Virus as a Successful Strategy for Breast Cancer Treatment

Marie-Claude Bourgeois-Daigneault; Lauren Elizabeth St-Germain; Dominic Guy Roy; Adrian Pelin; Amelia Sadie Aitken; Rozanne Arulanandam; Theresa Falls; Vanessa Garcia; Jean-Simon Diallo; John Cameron Bell

Disclosures

Breast Cancer Res. 2016;18(83) 

In This Article

Discussion

In this study, we demonstrated the compatibility of PAC, a standard-of-care chemotherapeutic agent for breast cancer, and MG1, an OV that is considered a promising and novel strategy for treating disseminated diseases like breast cancer. Our results not only show that treatments do not interfere with one another, but they can also perform even better when co-administered. Using three different syngeneic murine breast cancer models, we show a prolongation of survival for animals that received both treatments compared to either treatment alone (Fig. 6). These findings have potential implications for the future treatment of patients. Our data support clinical testing of the combination. Even if the patient's cancer has become resistant to the drug, it might still effectively enhance MG1 and at the very least, should not impair the viral treatment. Second, because the beneficial effects we observed were achieved using sub-lethal concentrations of PAC and knowing the various side effects of the drug in patients with cancer, it is tempting to suggest that using a lower concentration of PAC in combination with the virus would be a suitable strategy.

Interestingly, we found that two out of the three murine tumor cell lines and the human tumor cell lines that we tested were sensitized to viral infection by PAC (Fig. 2). Indeed, while EMT6 and 4 T1 cells produced more virus when pre-treated with the drug, the E0771 cell line was not affected. Our model is that PAC pre-treatment would block the secretion of antiviral factors like IFNβ by infected cells (Additional file 2: Figure S2B), thereby increasing virus infection. In line with this idea, both EMT6 and 4 T1 cells in which we see sensitization to the virus, but not the E0771 cells, which are refractory to this effect, demonstrated impaired production of the antiviral cytokine (Additional file 2: Figure S2B). Importantly, our results also show that while ex-vivo infection and treatment of patient breast cancer xenografts can inform us on the potential enhancement of the virus by the drug in specific patient samples (Fig. 4e), the lack of enhancement would not necessarily imply that both treatments would not be compatible. Indeed, increased production of virus is desirable, but the killing of the target tumor cells is what ultimately matters. Our data show that although the E0771 cell line does not demonstrate sensitization to the virus in the presence of PAC, complete killing of the cells was still observed at concentrations of PAC and MG1 that did not affect cell viability alone. Notably, the E0771 tumor model was the one in which we observed the highest percentage of cures with the treatment combination (Fig. 6c). This is most likely due to the greater sensitivity of the E0771 tumors to both single treatments alone compared to the two other tumor models (Fig. 6). Remarkably, while the EMT6 and 4 T1 tumors are slightly smaller compared to the control animals when treated with either the virus or the drug, the combination of both treatments was the only condition that was significantly different in terms of the ability to control tumor growth and prolong survival.

An interesting idea to explain the improved killing observed in vitro in the E0771 cell line would be that virus-induced factors may promote PAC killing. Indeed, it has been reported by Thorne and colleagues that oncolytic vaccinia virus induces the secretion of factors, including type I IFNs, which sensitize tumor cells to taxol.[13] Also, a similar mechanism was observed for the colchicine and VSV co-treatment.[11] This scenario would provide a mechanism by which even tumors that are refractory to the PAC-mediated sensitization to MG1 could still benefit from the combination. Of note, infection with vaccinia virus produces various anti-inflammatory factors,[20] including B18R which inhibits the activity of IFNs and could potentially minimize this effect, while MG1 and VSV do not encode these inhibitors, suggesting that the virus-mediated sensitization of tumor cells to PAC-mediated killing could be even greater.[7,8]

Another interesting application of our combination strategy would be to potentiate the production of virally-encoded transgenes. The engineering of oncolytic viruses has been shown to be a successful strategy for tumor-targeted gene delivery and improvement of treatment efficacy. Indeed, rhabdoviruses encoding antiviral suppressors to increase viral replication,[21] suicide genes to improve killing[22] or immune-stimulating cytokines to induce a greater anti-tumor immune response[23] have all been shown to control tumor growth more efficiently compared to the parental virus. Given that, along with the increased virus production, we also observed more GFP-positive cells and higher MFV (Fig 2b and c) and thus, greater transgene production, the co-treatment could potentially be even more beneficial using viruses that encode transgenes that mediate greater control of the tumors.

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