TMIC-61. DEVELOPMENT OF A NOVEL NOTCH-TARGETING ONCOLYTIC HSV FOR GBM TUMORS

Abstract Glioblastoma (GBM) is the most aggressive brain malignancy, which despite continuing worldwide efforts to develop new therapies, remains a deadly disease with limited treatment options. The NOTCH signaling pathway is often hyperactive in GBM tumors, and its activity contributes to tumor progression and resistance to treatment. The role of NOTCH signaling in tumor growth and resistance is well studied, but the significance of this pathway for immunotherapy of GBM is not very well understood. We have recently shown that NOTCH activation following virotherapy contributes to tumor regrowth and induces recruitment of monocytic MDSC cells into the tumor, which limit optimal immune activation to kill tumor cells. For this study, we have discovered a NOTCH interfering intracellular ligand (NIIL) that blocks NOTCH activation from inside glioma cells. RNA sequencing shows the expression of NIIL downregulates NOTCH signaling in vitro. To evaluate the effect of NIIL on virotherapy, we generated an oncolytic herpes simplex virus (oHSV) that also encodes for NIIL. This virus showed a slower spread in vitro but improved therapeutic efficacy in vivo in multiple models of intracranial tumors. In immune competent mice there was a significant improvement in the survival of mice treated with the NIIL-encoding virus, with a fraction of mice showing a complete response after a single treatment. Single-cell RNA sequencing analysis of immune infiltrates is ongoing to understand how NIIL impacts tumor microenvironment and anti-tumor immune therapy.