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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：
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.

摘要：本申请的总体目标是开发一种与oHSV结合的NOTCH阻断策略，安全地输送至颅内GBM以增强治疗效果而无神经毒性。正常 Notch信号在记忆加工和成人神经发生中起着重要作用。胶质母细胞瘤中 (GBM)NOTCH信号传导也与化疗耐药性的产生有关，辐射，并有助于与GBM相关的惨淡生存，GBM是一种与不到2 尽管接受了手术、放疗、替莫唑胺和肿瘤治疗，设备.本申请的总体目标是了解特异性NOTCH配体介导的免疫调节的影响。脑肿瘤oHSV治疗中的NOTCH激活。由于NOTCH信号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记忆发展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感染诱导肿瘤和肿瘤细胞中的NOTCH活化。相关巨噬细胞（TAM）。TAM的NOTCH活化导致诱导CCL 2，其募集单核细胞 MDSC对感染的肿瘤。虽然oHSV治疗唤醒了抗肿瘤功效，但这些单核细胞MDSC限制了抗肿瘤功效。免疫系统通过在肿瘤中培养免疫抑制环境而受益。已经显示不同的NOTCH配体对抗肿瘤免疫具有不同的作用。比如说， DLL 1介导的NOTCH激活对于T细胞成熟为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。虽然JAG 1和在较小程度上JAG 2诱导PD-1和PD-2，抑制T细胞免疫。因此，我们假设阻断JAG 1介导的信号传导可以增强病毒疗法诱导抗肿瘤免疫，并且其通过oHSV的瞬时表达不会产生神经系统免疫。小鼠的记忆缺陷。由于膜结合配体可以激活NOTCH信号传导和可溶性单体配体，配体可以抑制NOTCH信号传导，在这里，我们将测试阻断单个NOTCH配体介导的效应。 NOTCH活化对oHSV功效和抗肿瘤免疫性的影响（目的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ACV的敏感性以及对小鼠行为和记忆的影响。进一步我们已经发现oHSV与辐射的组合协同激活NOTCH信号传导。在aim 3中我们将评估这种病毒与辐射结合的效果。