Next Gen Virotherapy for GBM

GBM 的下一代病毒疗法

基本信息

批准号：
10467244
负责人：
Balveen Kaur
金额：
$ 53.64万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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：
2022-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10467244
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 Japan Lead Ligands 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 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 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：该应用程序的总体目标是制定一种与OHSV结合使用的凹口阻断策略安全地递送到颅内GBM，以增强没有神经毒性的治疗功效。在正常情况下大脑，Notch信号传导在记忆加工和成人神经发生中起着重要作用。在胶质母细胞瘤中（GBM）Notch信号传导也与化学疗法抗性的发展有关辐射，并导致与GBM相关的沮丧的生存，这种疾病少于2 尽管手术，辐射，替莫唑胺和肿瘤治疗场进行治疗，但仍有中位生设备。该应用的总体目标是了解特定的Notch配体介导的影响 OHSV疗法的Notch激活脑肿瘤。由于Notch信号传导在大脑中起着重要作用在记忆加工和成人神经发生中，我们还将评估阻断特定配体对颅内使用的记忆发展和安全性。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的凹口激活相关巨噬细胞（TAM）。 TAM的缺口激活导致CCL2诱导单核细胞 MDSC被感染的肿瘤。虽然OHSV处理唤醒了抗肿瘤功效，但这些单核细胞限制通过教育肿瘤中的免疫抑制环境，免疫治疗益处。已经表明，不同的缺口配体对抗肿瘤免疫有不同的影响。例如， DLL1介导的Notch激活对于T细胞成熟到记忆细胞及其过表达很重要增强T细胞活性和抗肿瘤免疫力。而JAG1，较小的JAG2，诱导PD-1和抑制T细胞免疫。因此，我们假设JAG1介导的信号的阻塞应增强病毒疗法诱导的抗肿瘤免疫，其通过OHSV的瞬时表达不会产生神经系统小鼠的记忆不足。由于，膜结合的配体可以激活Notch信号传导和可溶性单体配体可以抑制Notch信号，在这里我们将测试阻断单个缺口配体介导的效果 OHSV功效和抗肿瘤免疫的缺口激活（AIM 1）。在AIM 2中，我们将创建一个可以有效地阻断病毒引起的配体特异性Notch信号传导，以增强病毒诱导的抗肿瘤免疫。该病毒还将评估以确保安全性，对ACV的敏感性以及对小鼠行为和记忆的影响。更远我们发现，OHSV与辐照的组合协同激活Notch信号。在目标3中我们将评估该病毒与辐照结合的作用。