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Next Gen Virotherapy for GBM

GBM 的下一代病毒疗法

基本信息

批准号：
10818683
负责人：
Balveen Kaur
金额：
$ 52.96万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10818683
关键词：
ADAMTS Affect Animals Behavior Brain Brain Neoplasms CCL2 gene Cell Maintenance Cell Maturation Cell Survival Cells Chemotherapy and/or radiation Data Development Devices Disease Drug usage Environment FDA approved Glioblastoma Glioma Goals Grant Growth Herpesvirus 1 Human Immune Immunity Immunocompetent Immunotherapeutic agent Individual Infection Intracranial Neoplasms Invaded Japan Lead Ligand Binding Ligands Marketing Mediating Membrane Memory Memory impairment Modeling Mus Myeloid Cells Myeloid-derived suppressor cells Nervous System Physiology Neurologic Notch Signaling Pathway Oncolytic Oncolytic viruses Operative Surgical Procedures Oral Outcome Pathway interactions Patients Peptide Hydrolases Peptides Phenotype Play Prognosis Public Health Radiation Radiation therapy Resistance development Role Safety Signal Transduction Simplexvirus T cell differentiation T-Lymphocyte Testing Therapeutic Toxic effect Transcriptional Activation Treatment Efficacy Tumor Immunity Tumor-associated macrophages Virotherapy Virus adult neurogenesis angiogenesis cancer cell clinical development cytotoxicity efficacy evaluation gamma secretase improved inhibitor irradiation melanoma memory process monocyte monomer negative affect neoplastic cell notch protein novel strategies novel therapeutics oncolytic herpes simplex virus oncolytic virotherapy overexpression programmed cell death protein 1 receptor recruit response stem cells stemness synergism temozolomide tumor tumor progression virus development

项目摘要

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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