IMMU-47. IMMUNOGENIC AND IMMUNOSUPPRESSIVE ASPECTS OF HSV-TK/GCV-MEDIATED SUICIDE GENE THERAPY IN GLIOMA CELLS

Abstract

Abstract Suicide Gene therapy (SGT) has been regarded as a promising experimental treatment modality for high-grade gliomas for several decades. However, large-scale clinical trials have failed so far. One hypothesis behind this failure is that, even though SGT directly kills the bulk of the tumor cells, it fails to activate an efficient anti-tumor immune response. Indeed, despite extensive research on SGT, the mechanism of cell death caused by SGT and its immunogenic significance are largely unknown. The most prominent form of SGT— HSV-TK/GCV— for example, is known to kill tumor cells mostly by apoptosis. The immunogenicity of apoptosis in general is controversial and not yet fully explored, especially in the context of SGT. We studied the immunogenic nature of cell death caused by HSV-TK/GCV with two widely used mouse glioma models. To exclude the potential influence of viral vectors on the immune system, we used genetically engineered tumor cells that expresses HSV-TK gene. After orthotopic tumor modelling and SGT with HSV-TK/VGCV, we analyzed the change in immune landscape by using ELISPOT, IHC, FACS and Hyperion in both models. Firstly, we observed that the efficacy of SGT is entirely different in the two glioma models. While in one model tumor growth is only decreased, SGT is curative in the second model. In the non-responding model, an immunosuppressive tumor microenvironment after SGT is observed. Further investigation of the responding model shows that the successful cure is dependent on the availability of an active immune system. We have also identified that the resultant anti-tumor immunity following SGT in this model is mounted by T cells. In conclusion, our data suggest that the immunogenic nature of SGT shows intertumoral heterogeneity and warrants more research to identify the inherent determining factors and mechanisms thereof.