Next Gen Virotherapy for GBM

摘要： 这个应用程序的总体目标是开发一种与OHSV相结合的缺口阻断策略，它可以 被安全地输送到颅内基底膜，以增强治疗效果，且没有神经毒性。在正常情况下 在大脑中，Notch信号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)Noch信号也与化疗耐药和 辐射，并导致与GBM相关的悲惨生存，GBM是一种与不到2 接受手术、放疗、替莫唑胺和肿瘤治疗的中位生存期 设备。本应用的总体目标是了解特定缺口配体介导的影响 脑肿瘤OHSV治疗中的缺口激活。因为缺口信号在大脑中扮演着重要的角色 在记忆处理和成年神经发生中，我们还将评估阻断特定配体对 脑部使用的记忆力发展和安全性。 在我们的初步结果中，我们已经确认OHSV感染诱导肿瘤和肿瘤中的缺口激活。 相关巨噬细胞()。TAMS的缺口激活导致CCL2的诱导，从而招募单核细胞 骨髓间充质干细胞向感染肿瘤转移。虽然OHSV治疗唤醒了抗肿瘤的效果，但这些单核细胞MDSCs限制了 免疫治疗的好处在于培养了肿瘤中的免疫抑制环境。 研究表明，不同的缺口配体具有不同的抗肿瘤免疫作用。例如, DLL1介导的缺口激活对T细胞成熟为记忆细胞及其过度表达具有重要意义 增强T细胞活性和抗肿瘤免疫力。而JAG1和JAG2在较小程度上诱导PD-1和 抑制T细胞免疫。因此，我们假设对JAG1介导的信号传导的阻断应该加强 病毒治疗诱导抗肿瘤免疫，OHSV的瞬时表达不会产生神经功能障碍 小鼠的记忆缺陷。由于膜结合配体可以激活缺口信号和可溶性单体 配体可以抑制Noch信号转导，这里我们将测试阻断单个Noch配体介导的效果 缺口激活对OHSV疗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，它可以 有效阻断病毒诱导的配体特异性缺口信号，增强病毒诱导的抗肿瘤免疫。 还将评估这种病毒的安全性、对无环鸟苷的敏感性以及对小鼠行为和记忆的影响。进一步 我们发现OHSV与辐射的结合可以协同激活Noch信号。在AIM 3中 我们将结合辐射来评估这种病毒的效果。

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.