IT-27 * ONCOLYTIC ADENOVIRUSES-MEDIATED IMMUNE RESPONSES IN SYNGENEIC MURINE GLIOMA MODEL

Abstract

INTRODUCTION: Oncolytic adenovirus has been developed as a new experimental anticancer agent currently in clinical trials for glioma. Recent evidence suggests oncolytic viruses also have a therapeutic feature of inducing antitumor immune responses. Here we provide evidence that injection of oncolytic adenoviruses into established murine glioma leads to a conversion of immunosuppressive into immunostimulatory tumor environment. METHODS: Stereotactic orthotopic murine GL261 glioma was established in syngeneic immune competent mice. AdCMVΔ24 virus that has been shown to exhibit oncolytic effects on GL261 cells previously by our group was selected in the current studies. Using GL261 murine glioma model along with AdCMVΔ24, we evaluated the effects of viral treatment on generation of immune responses locally (in brain) and systemically (in cervical lymph nodes (cLNs) and spleens) upon viral injection into tumors. RESULTS: At 72hr post treatment, we observed a significant intracranial increase of both macrophages and NK cells. More importantly, we found that AdCMVΔ24 treatment decreased intracranial regulatory T cells (CD4+Foxp3+) at 72hr, 1 week, even at 2 weeks post viral treatment, whereas this was not observed in cLNs and spleens. In contrast to Treg cells, the frequency of CD3+CD8+ T cells were increased at 1 week and 2 weeks post treatment. We also found an increased frequency of IFN-g producing CD8+ cells, in cLNs as early as at 72hr and in brains at 2 weeks post treatment. Further, our studies demonstrated that intratumoral viral injection leads an increase of a ratio of CD4+IFN-g+T cells per CD4+Foxp3+ T cells. CONCLUSIONS: Taken together, these results suggest that intratumoral oncolytic adenovirus treatment may shift the immune response from suppressive to stimulatory through modulation of Treg cells, which could have significant impacts on the development of CRADs-based novel effective antiglioma immunotherapies.