Type-1 Antigen Presenting Cells in CNS Tumors - Key to Efficient Anti-Tumor T-Cel
CNS 肿瘤中的 1 型抗原呈递细胞 - 高效抗肿瘤 T 细胞的关键
基本信息
- 批准号:8518922
- 负责人:
- 金额:$ 2.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-05 至
- 项目状态:未结题
- 来源:
- 关键词:AcidsAdjuvantAntigen-Presenting CellsAntigensAutoimmune encephalitisBone MarrowCXCL10 geneCXCL9 geneCarboxymethylcelluloseCellsCentral Nervous System NeoplasmsCervical lymph node groupCharacteristicsClinical TrialsCollaborationsCross-PrimingDataDendritic CellsDevelopmentEngineeringEnvironmentExhibitsGlioblastomaGliomaHistologicHome environmentHomingHumanImmunotherapeutic agentImmunotherapyInstructionInterferon-alphaInterferonsInterleukin-12LeadLigandsLysineMalignant NeoplasmsMediatingMelanoma CellMicrogliaModelingMolecularMusNeuraxisOncolyticOperative Surgical ProceduresPTGS2 genePeripheralPharmaceutical PreparationsPhasePhenotypePoly I-CPoly ICLCProductionResearch PersonnelSiteSystemT cell responseT-LymphocyteToxic effectTreatment EfficacyUp-RegulationVaccinationVaccine DesignVaccinesVaccinia virusbasecelecoxibchemokinecytokineimprovedin vivoinhibitor/antagonistmacrophagenoveloutcome forecastpre-clinicalprogramssuccesstumorvaccine efficacyvaccine safety
项目摘要
Despite recent advances made in surgical, radiological and chemotherapeutic approaches, the prognosis of
central nervous system (CMS) malignancies remains dismal. Although the safety of vaccine-approaches for
CNS malignancies has been established in early phase clinical trials, the success of a vaccine strategy will
depend critically on the ability of effector T-cells to home to CNS tumors and exert anti-tumor effects. Based
on our recent studies, efficient CNS tumor-homing is characteristic of CTLs with a type-1 phenotype (Tc1) as
opposed to ones with the type-2 phenotype (Tc2), and appears to be mediated by a type-1 chemokine,
CXCL10. In addition, direct intratumoral delivery of dendritic cells (DC) ex vivo engineered to secrete
interferon (IFN)-alpha further enhances Tc1-homing via up-regulation of a type-1 chemokine CXCL10/IP-10
in the tumor environment. While CNS-tumor infiltrating antigen presenting cells (APCs), such as microglia
and macrophage, exhibit type-2 (M2) phenotype, our data suggest that substantial improvements in the
efficacy of vaccine strategies can be achieved by efforts to convert the type-2-deviated microenvironment of
central nervous system (CNS) tumors. Hence, we will focus on potential means of converting a type-2 to a
type-1 microenvironment in preclinical mouse CNS tumor models, including a novel de novo mouse glioma
model that phenotypically and histologically resembles human glioblastoma multiforme (GBM). Our central
hypothesis is that the efficacy of T-cell based anti-CNS tumor therapy can be improved by: (a) intratumoral
administration of a potent class of DCs expressing type-1 cytokines/chemokines (DC1), (b) administration of
type-1 promoting factors, including the adjuvant polyinosinic-polycytidylic acid stabilized by lysine and
carboxymethylcellulose (poly-ICLC), or (c) combination of both Dd-delivery and administration of type-1
promoting factors. We will evaluate the following Specific Aims (SA). SA 1: Determine whether intratumoral
delivery of ex vivo generated DC1 can enhance the therapeutic efficacy of systemic type-1 CTL (Tc1)
therapy; SA 2: Determine whether delivery of type-1 promoting factors can lead to M1 phenotype of CNS
tumor-infiltrating ARC s. SA 3: Determine whether the re-directed CNS-APCs enhance the therapeutic
efficacy of Tc1 therapy and/or peripheral DC 1-based vaccinations.
RELEVANCE (See instructions):
尽管最近在手术、放射和化疗方法方面取得了进展,
中枢神经系统(CMS)恶性肿瘤仍然令人沮丧。虽然疫苗的安全性,
中枢神经系统恶性肿瘤已在早期临床试验中确立,疫苗策略的成功将
关键取决于效应T细胞归巢CNS肿瘤并发挥抗肿瘤作用的能力。基于
在我们最近的研究中,有效的CNS肿瘤归巢是具有1型表型(Tc 1)的CTL的特征,
与具有2型表型(Tc 2)的那些相反,并且似乎由1型趋化因子介导,
CXCL 10.此外,直接肿瘤内递送树突状细胞(DC)离体工程化以分泌肿瘤特异性抗原。
干扰素-α通过上调1型趋化因子CXCL 10/IP-10进一步增强Tc 1归巢
在肿瘤环境中。而CNS-肿瘤浸润性抗原呈递细胞(APC),如小胶质细胞,
和巨噬细胞,表现出2型(M2)表型,我们的数据表明,
疫苗策略的有效性可以通过努力转化2型偏离的微环境来实现。
中枢神经系统(CNS)肿瘤。因此,我们将重点关注将类型2转换为类型2的潜在方法。
临床前小鼠CNS肿瘤模型中的1型微环境,包括一种新的新生小鼠神经胶质瘤
表型和组织学上类似于人多形性胶质母细胞瘤(GBM)的模型。我们的中央
假设基于T细胞的抗CNS肿瘤疗法的功效可以通过以下方式改善:(a)肿瘤内
施用表达1型细胞因子/趋化因子(DC 1)的有效类别的DC,(B)施用
1型促进因子,包括由赖氨酸稳定的佐剂聚肌苷-聚胞苷酸,
羧甲基纤维素(聚-ICLC),或(c)DD-递送和1型胶原蛋白的施用的组合
促进因素。我们将评估以下具体目标(SA)。SA 1:确定肿瘤内
递送离体产生的DC 1可以增强系统性1型CTL(Tc 1)的治疗功效,
治疗; SA 2:确定1型促进因子的递送是否可导致CNS的M1表型
肿瘤浸润性ARC。SA 3:确定重定向的CNS-APC是否增强了治疗性免疫应答。
Tc 1治疗和/或基于外周DC 1的疫苗接种的有效性。
相关性(参见说明):
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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{{ truncateString('Hideho Okada', 18)}}的其他基金
Development of novel synNotch CART cell therapy in adult patients with recurrent EGFRvIII+ glioblastoma
开发新型 synNotch CART 细胞疗法治疗复发性 EGFRvIII 胶质母细胞瘤成人患者
- 批准号:
10305133 - 财政年份:2021
- 资助金额:
$ 2.28万 - 项目类别:
Development of novel synNotch CART cell therapy in adult patients with recurrent EGFRvIII+ glioblastoma
开发新型 synNotch CART 细胞疗法治疗复发性 EGFRvIII 胶质母细胞瘤成人患者
- 批准号:
10487528 - 财政年份:2021
- 资助金额:
$ 2.28万 - 项目类别:
Development of novel synNotch CART cell therapy in adult patients with recurrent EGFRvIII+ glioblastoma
开发新型 synNotch CART 细胞疗法治疗复发性 EGFRvIII 胶质母细胞瘤成人患者
- 批准号:
10689805 - 财政年份:2021
- 资助金额:
$ 2.28万 - 项目类别:
Glioma immunotherapy targeting IDH mutation-derived epitope and immunosuppression
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- 批准号:
10174862 - 财政年份:2018
- 资助金额:
$ 2.28万 - 项目类别:
Glioma immunotherapy targeting IDH mutation-derived epitope and immunosuppression
针对 IDH 突变衍生表位和免疫抑制的胶质瘤免疫治疗
- 批准号:
10436184 - 财政年份:2018
- 资助金额:
$ 2.28万 - 项目类别:
Preclinical development of breakthrough immunotherapy for brain tumors
脑肿瘤突破性免疫疗法的临床前开发
- 批准号:
10551829 - 财政年份:2017
- 资助金额:
$ 2.28万 - 项目类别:
Preclinical development of breakthrough immunotherapy for brain tumors
脑肿瘤突破性免疫疗法的临床前开发
- 批准号:
10632441 - 财政年份:2017
- 资助金额:
$ 2.28万 - 项目类别:
Preclinical development of breakthrough immunotherapy for brain tumors
脑肿瘤突破性免疫疗法的临床前开发
- 批准号:
10059272 - 财政年份:2017
- 资助金额:
$ 2.28万 - 项目类别:
Preclinical development of breakthrough immunotherapy for brain tumors
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10304142 - 财政年份:2017
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Phase I Vaccine Study using Brain Tumor Initiating Cells in WHO Grade II Gliomas
使用 WHO II 级神经胶质瘤中的脑肿瘤起始细胞进行 I 期疫苗研究
- 批准号:
8754952 - 财政年份:2014
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