Utilizing oncolytic vaccinia virus to modulate the tumor microenvironment

Oncolytic viruses are viruses which lyse tumor cells and stimulate a patient specific anti-tumor and anti-viral immune response. While one oncolytic virus has received FDA approval, clinical success has been limited. To design better oncolytics, we must improve our understanding of their mechanism of action and resistance. In this dissertation, I report that the infection of lymphocytes in the tumor by oncolytic vaccinia virus (VV) is important for the anti-tumor immune response. VV infects suppressive exhausted T cells and leads to their death and inhibiting this death decreases animal survival. I also found that oncolytic vaccinia-resistant tumors have high levels of intratumoral TGFβ. By engineering oncolytic vaccinia to deliver a TGFβR inhibitor, we rendered these tumors sensitive to treatment. Inhibiting TGFβ in the tumor with the immune stimulatory effects of VV reduced the suppression of regulatory T cells, resulting in increased effector T cell function. Overall, we show that oncolytic viruses stimulate an inflammatory immune response in both sensitive and resistant tumor models. In tumors resistant to therapy, it is also necessary to target the suppressive cell types for deletion or reprogramming, to promote a response to VV therapy. While traditionally, oncolytic virus combinations have added more stimulatory therapies, these data suggest the importance of also targeting resistance mechanisms when engineering or combining oncolytics with other therapies.