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:
- 金额:$ 52.96万
- 依托单位:
- 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:
- 关键词:ADAMTSAffectAnimalsBehaviorBrainBrain NeoplasmsCCL2 geneCell MaintenanceCell MaturationCell SurvivalCellsChemotherapy and/or radiationDataDevelopmentDevicesDiseaseDrug usageEnvironmentFDA approvedGlioblastomaGliomaGoalsGrantGrowthHerpesvirus 1HumanImmuneImmunityImmunocompetentImmunotherapeutic agentIndividualInfectionIntracranial NeoplasmsInvadedJapanLeadLigand BindingLigandsMarketingMediatingMembraneMemoryMemory impairmentModelingMusMyeloid CellsMyeloid-derived suppressor cellsNervous System PhysiologyNeurologicNotch Signaling PathwayOncolyticOncolytic virusesOperative Surgical ProceduresOralOutcomePathway interactionsPatientsPeptide HydrolasesPeptidesPhenotypePlayPrognosisPublic HealthRadiationRadiation therapyResistance developmentRoleSafetySignal TransductionSimplexvirusT cell differentiationT-LymphocyteTestingTherapeuticToxic effectTranscriptional ActivationTreatment EfficacyTumor ImmunityTumor-associated macrophagesVirotherapyVirusadult neurogenesisangiogenesiscancer cellclinical developmentcytotoxicityefficacy evaluationgamma secretaseimprovedinhibitorirradiationmelanomamemory processmonocytemonomernegative affectneoplastic cellnotch proteinnovel strategiesnovel therapeuticsoncolytic herpes simplex virusoncolytic virotherapyoverexpressionprogrammed cell death protein 1receptorrecruitresponsestem cellsstemnesssynergismtemozolomidetumortumor progressionvirus 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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Balveen Kaur其他文献
Balveen Kaur的其他文献
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{{ truncateString('Balveen Kaur', 18)}}的其他基金
Optimizing oncolytic virus therapy for glioblastoma
优化胶质母细胞瘤的溶瘤病毒治疗
- 批准号:
9807942 - 财政年份:2019
- 资助金额:
$ 52.96万 - 项目类别:
Optimizing oncolytic virus therapy for glioblastoma
优化胶质母细胞瘤的溶瘤病毒治疗
- 批准号:
10618742 - 财政年份:2019
- 资助金额:
$ 52.96万 - 项目类别:
Enhancing viral oncolysis with vasculostatin gene delivery
通过血管抑素基因传递增强病毒溶瘤作用
- 批准号:
9900732 - 财政年份:2017
- 资助金额:
$ 52.96万 - 项目类别:
Project 3: Circumventing extracellular Adenosine barrier to oncolytic virotherapy
项目3:绕过溶瘤病毒疗法的细胞外腺苷屏障
- 批准号:
10712282 - 财政年份:2013
- 资助金额:
$ 52.96万 - 项目类别:
Project 3: Notch signaling in oHSV therapy for GBM
项目 3:oHSV 治疗 GBM 中的 Notch 信号传导
- 批准号:
10491211 - 财政年份:2013
- 资助金额:
$ 52.96万 - 项目类别:
Project 3: Notch signaling in oHSV therapy for GBM
项目 3:oHSV 治疗 GBM 中的 Notch 信号传导
- 批准号:
10019365 - 财政年份:2013
- 资助金额:
$ 52.96万 - 项目类别:
Project 3: Notch signaling in oHSV therapy for GBM
项目 3:oHSV 治疗 GBM 中的 Notch 信号传导
- 批准号:
10251084 - 财政年份:2013
- 资助金额:
$ 52.96万 - 项目类别:
Enhancing Viral Oncolysis with Vasculostatin Gene Delivery
通过血管抑素基因传递增强病毒溶瘤作用
- 批准号:
8638899 - 财政年份:2011
- 资助金额:
$ 52.96万 - 项目类别:
Enhancing Viral Oncolysis with Vasculostatin Gene Delivery
通过血管抑素基因传递增强病毒溶瘤作用
- 批准号:
8450666 - 财政年份:2011
- 资助金额:
$ 52.96万 - 项目类别:
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