Abstract: The overall goal of this application is to develop a NOTCH blocking strategy in combination with oHSV that can be safely delivered to intracranial GBM to enhance therapeutic efficacy without neurologic toxicity. In the normal brain, Notch signaling plays a significant role in memory processing and adult neurogenesis. In glioblastoma (GBM) NOTCH signaling has also been implicated in the development of resistance to chemotherapy and radiation, and contributes to the dismal survival associated with GBM, a disease associated with a less than 2 year median survival despite treatment with surgery, radiation, temozolomide, and with tumor treating field device. The overall goal of this application is to understand the impact of specific NOTCH ligand mediated NOTCH activation on oHSV therapy for brain tumors. Since NOTCH signaling plays a significant role in the brain in memory processing and adult neurogenesis, we will also evaluate the impact of blocking specific ligands on memory development and safety for intracranial usage. In our preliminary results we have identified that oHSV infection induces NOTCH activation in tumor and tumor associated macrophages (TAM). NOTCH activation of TAMs results in induction of CCL2 that recruits monocytic MDSCs to infected tumors. While oHSV treatment awakens anti-tumor efficacy, these monocytic MDSCs limit the immunotherapeutic benefit by educating an immune-suppressive environment in tumors. It has been shown that different NOTCH ligands have different effects on anti-tumor immunity. For example, DLL1-mediated NOTCH activation is important for T cell maturation into memory cells and its overexpression augments T cell activity and anti-tumor immunity. While JAG1, and to a lesser extent JAG2, induce PD-1 and suppress T cell immunity. Thus, we hypothesize that blockade of JAG1 mediated signaling should enhance virotherapy induced anti-tumor immunity, and its transient expression by an oHSV would not create a neurologic memory deficit in mice. Since, membrane bound ligands can activate NOTCH signaling and soluble monomeric ligands can inhibit NOTCH signaling, here we will test the effect of blocking individual NOTCH ligand mediated NOTCH activation on oHSV efficacy and anti-tumor immunity (Aim 1). In aim 2 we will create an oHSV that can effectively block virus induced ligand specific NOTCH signaling to augment virus induced anti-tumor immunity. This virus will also be evaluated for safety, sensitivity to ACV, and effect on mouse behavior and memory. Further we have found that combination of an oHSV with irradiation synergistically activates NOTCH signaling. In aim 3 we will evaluate the effect of this virus in combination with irradiation.
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