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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.

抽象的：该应用的总体目标是开发一种与 oHSV 结合的 NOTCH 阻断策略，该策略可以安全地递送至颅内 GBM 以增强治疗效果而无神经毒性。在正常情况下在大脑中，Notch 信号在记忆处理和成人神经发生中发挥着重要作用。在胶质母细胞瘤中 (GBM) NOTCH 信号传导也与化疗耐药性的发展有关辐射，并导致与 GBM 相关的令人沮丧的生存率，GBM 是一种与小于 2 相关的疾病尽管接受手术、放疗、替莫唑胺和肿瘤治疗领域的治疗，但年中位生存期设备。本申请的总体目标是了解特定 NOTCH 配体介导的影响 oHSV 脑肿瘤治疗中的 NOTCH 激活。由于 NOTCH 信号在大脑中发挥着重要作用在记忆处理和成人神经发生中，我们还将评估阻断特定配体对记忆发育和颅内使用的安全性。在我们的初步结果中，我们已经确定 oHSV 感染会诱导肿瘤和肿瘤中的 NOTCH 激活。相关巨噬细胞（TAM）。 TAM 的 NOTCH 激活导致 CCL2 的诱导，从而募集单核细胞 MDSC 感染肿瘤。虽然 oHSV 治疗唤醒了抗肿瘤功效，但这些单核细胞 MDSC 限制了通过在肿瘤中培养免疫抑制环境来获得免疫治疗益处。研究表明，不同的NOTCH配体对抗肿瘤免疫具有不同的作用。例如， DLL1介导的NOTCH激活对于T细胞成熟为记忆细胞及其过度表达非常重要增强 T 细胞活性和抗肿瘤免疫力。而 JAG1 以及较小程度的 JAG2 会诱导 PD-1 和抑制T细胞免疫。因此，我们假设 JAG1 介导的信号传导的阻断应该增强病毒疗法诱导抗肿瘤免疫，并且 oHSV 的短暂表达不会产生神经系统疾病小鼠的记忆缺陷。因为，膜结合配体可以激活 NOTCH 信号传导和可溶性单体配体可以抑制NOTCH信号传导，这里我们将测试阻断单个NOTCH配体介导的效果 NOTCH 激活对 oHSV 功效和抗肿瘤免疫的影响（目标 1）。在目标 2 中，我们将创建一个 oHSV 有效阻断病毒诱导的配体特异性NOTCH信号传导，以增强病毒诱导的抗肿瘤免疫。还将评估该病毒的安全性、对苹果醋的敏感性以及对小鼠行为和记忆的影响。更远我们发现 oHSV 与辐射的组合可协同激活 NOTCH 信号传导。目标 3 我们将评估这种病毒与辐射相结合的效果。