IMPS-21EFFECT OF rQNestin 34.5 ONCOLYTIC HERPES VIRUS ON IMMUNE CHECKPOINT GENE EXPRESSION IN GLIOBLASTOMA CELLS AND EVALUATION OF THERAPEUTIC EFFICACY

Abstract

There has been a recent surge of interest in cancer immunotherapies due to newly FDA approved immunologic treatments based on targeting immune checkpoint inhibition pathways. Multiple preclinical and clinical trials combining immunostimulatory approaches with immune checkpoint inhibition are also underway, reinforced by fairly dramatic anticancer responses in animal models and early clinical human trials. Because oncolytic viruses (OVs) can lead to improved presentation of tumor antigens, they may be potentially useful in combination with immune checkpoint approaches. We have therefore investigated the potential of combining the Herpes OV (rQNestin 34.5) with immune checkpoint inhibition in glioblastoma models. rQNestin 34.5 is an OV with enhanced potency and tumor specificity, which will be tested in a Phase1 trial for recurrent glioblastoma in the near future. In vitro studies showed that the immune checkpoint ligand PD-L1 is expressed across a panel of human conventional and stem-like glioblastoma-derived cells (GSCs) and that cell surface PD-L1 is consistently up-regulated 24 hours after infection with rQNestin 34.5. This effect is most pronounced in GSCs of the mesenchymal subclass compared with proneural, and was not observed with other inducers of cell death such as staurosporine, and therefore may be due to direct effects of the OV treatment. We then showed that PD-L1 levels in glioblastoma cells are linked to increases of cytokine levels (i.e. interferon-g). These studies show that infection of cells with rQNestin 34.5 could lead to increased PD-L1 expression, thus providing a strong rationale for co-administration of OV with immune checkpoint blockade. Our initial studies using this combinatorial approach in immunocompetent mouse models demonstrate a significant and striking benefit of combined treatment with rQNestin34.5 and anti-PD-1 antibodies. This data suggests that immune checkpoint blockade combined with OV treatment should be developed for future clinical trials in glioblastoma.