Chemo-immunotherapy strategy for pediatric high grade glioma
儿童高级别胶质瘤的化学免疫治疗策略
基本信息
- 批准号:10296214
- 负责人:
- 金额:$ 42.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-15 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:ATRX geneAffectAgonistApolipoprotein A-IBiological AssayBloodBlood - brain barrier anatomyBone MarrowBrainBrain NeoplasmsCD8-Positive T-LymphocytesCause of DeathCaveolaeCell DeathCell surfaceCellsCerebral hemisphereChemotherapy and/or radiationChildhoodChildhood Brain NeoplasmChildhood GliomaCholesterolDNA DamageDNA RepairDNA Repair PathwayDataDevelopmentDisease ProgressionDrug Delivery SystemsEndocytosisExcisionExhibitsGene ExpressionGeneticGenetic EngineeringGenetically Engineered MouseGliomaHigh Density LipoproteinsHistonesHumanImmuneImmunityImmuno-ChemotherapyImmunologic MemoryImmunotherapeutic agentImpairmentImplantIn VitroIonizing radiationLesionLeucocytic infiltrateMalignant Childhood NeoplasmMalignant neoplasm of brainMediatingMembrane MicrodomainsModalityModelingMolecularMusMutationNonhomologous DNA End JoiningPatientsPatternPharmaceutical PreparationsPhenotypePhospholipidsPre-Clinical ModelPredispositionRadiationRecurrenceReportingResearchResistanceRodentRodent ModelSR-B proteinsSafetySiteSleeping BeautySubgroupSystemT cell responseTLR9 geneTP53 Gene InactivationTP53 geneTestingTherapeuticTimeTransposaseTreatment EffectivenessTreatment EfficacyVariantbaseblood-brain barrier permeabilizationbrain cellbrain parenchymacaveolin 1chemotherapeutic agentchemotherapyclinical translationcytotoxicitydraining lymph nodeeffective therapyexperimental studyhomologous recombinationhuman modelimmunogenic cell deathin vitro Modelin vivoinhibitor/antagonistlocal drug deliverymouse modelnanodiskneoplastic cellnovel therapeuticspeptidomimeticsresponsestandard of carestem cellstherapy outcometreatment responsetumortumor microenvironmenttumor progressionuptakeyoung adult
项目摘要
Abstract
Pediatric brain tumors are the leading cause of death in children with cancer in the U.S. Among them, pediatric
high-grade gliomas (pHGGs) are one of the most common and aggressive forms of brain cancer, with a median
survival of 9-15 months.1-3 One of the prominent subgroups of pHGG that arises in cerebral hemispheres
encodes for G34R/V substitutions in the histone H3F3A, along with ATRX and TP53 inactivating mutations.
The current standard of care, consisting of tumor resection followed by radiation and chemotherapy,1-4 only
leads to a modest increase in median survival. One of the reasons for the limited therapeutic outcomes is
tumor recurrence, caused by the spread of pHGG cells that infiltrate the brain.1-4 Treatment effectiveness for
pHGG has also been limited due to the blood-brain barrier (BBB),5 which precludes the efficient delivery of
chemotherapeutic compounds to the tumor mass. Therapeutic strategies involving local delivery of
chemotherapeutic agents to the tumor are emerging as attractive approaches. To explore novel therapeutic
modalities for the G34R/V pHGG subtype, we developed a de novo mouse model harboring the genetic lesions
using the Sleeping Beauty (SB) transposase-mediated system.6-8 Our preliminary data demonstrate that the
H3.3G34R mutation reduces the expression of genes involved with DNA repair, rendering the cells more
susceptible to ionizing radiation in vivo and to DNA damage sensitizers such as Olaparib, a PARP inhibitor. In
this application, we propose to deliver Olaparib into the TME using high-density lipoprotein (HDL)-mimicking
nanodiscs (NDs) that can be specifically internalized into tumor cells via scavenger receptor class B-1 (SR-
B1) and caveolae lipid rafts endocytosis.9 We observed that SR-B1 is expressed in H3.3G34R pHGG
neurospheres (NS) derived from the SB model, as well as in H3.3G34R pHGG patient-derived cells. In this
study, we will develop chemo-immunotherapy delivery vehicles based on sHDL NDs loaded with CpG, a Toll-
like receptor 9 (TLR9) agonist, together with Olaparib, a chemotherapeutic agent, for targeting H3.3G34R
pHGG. We demonstrated that local delivery of sHDL NDs loaded with chemo-immunotherapeutics, in an
intracranial syngeneic mouse glioma model, elicited tumor regression and anti-tumor CD8+ T cell responses
in the brain tumor microenvironment (TME) without overt off-target effects.10 These data indicate that sHDL
NDs are an attractive drug delivery platform for pHGG, which we hypothesize will result in tumor regression
and long-term survival. The proposed delivery system has significant potential for clinical translation.
摘要
儿童脑瘤是美国儿童癌症死亡的主要原因。其中,儿童脑瘤
高级别胶质瘤(PHGG)是最常见和最具侵袭性的脑癌之一,中位数
存活9-15个月1-3出现在大脑半球的PHGG的显著亚群之一
编码组蛋白H3F3A中的G34R/V替换,以及ATRX和TP53失活突变。
目前的护理标准,包括肿瘤切除,然后进行放疗和化疗,仅1-4
导致中位存活率略有增加。治疗效果有限的原因之一是
肿瘤复发,由渗入大脑的PHGG细胞扩散引起。1-4治疗效果
由于血脑屏障(BBB),PHGG也受到限制,5这排除了有效的递送
化疗化合物对肿瘤肿块的影响。涉及局部递送的治疗策略
治疗肿瘤的化疗药物正在成为吸引人的治疗方法。探索新的治疗方法
对于G34R/V PHGG亚型,我们建立了一个携带遗传损伤的新生小鼠模型
使用睡美人(SB)转座酶介导的系统。6-8我们的初步数据表明
H3.3G34R突变降低了DNA修复相关基因的表达,使细胞
对体内电离辐射和DNA损伤敏感剂敏感,如PARP抑制剂奥拉帕利布。在……里面
在这一应用中,我们建议使用模拟高密度脂蛋白(HDL)的方法将奥拉帕利布输送到TME中
可以通过清道夫受体B-1类(SR-1)特异性地内化到肿瘤细胞中的纳米盘(NDS)
9我们观察到SR-B1在H3.3G34R PHGG中有表达
神经球(NS)来自SB模型,以及H3.3G34R PHGG患者来源的细胞。在这
研究,我们将开发基于sHDLNDS装载CpG的化疗免疫治疗载体,一种通行费-
TLR9激动剂联合化疗药物奥拉帕利靶向H3.3G34R
PHGG。我们证明了携带化学免疫疗法的sHDLNDS的局部递送在一个
脑内同基因小鼠脑胶质瘤模型诱导的肿瘤消退和抗肿瘤CD8+T细胞反应
在脑肿瘤微环境(TME)中,没有明显的脱靶效应。10这些数据表明,sHDL
NDS是PHGG的一个有吸引力的药物传递平台,我们假设它将导致肿瘤消退
以及长期的生存。拟议的递送系统在临床翻译方面具有巨大的潜力。
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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Maria G Castro其他文献
Maria G Castro的其他文献
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{{ truncateString('Maria G Castro', 18)}}的其他基金
Systemic Delivery of Targeted Bi-Compartmental Nanoparticles for Glioblastoma Therapeutics
用于胶质母细胞瘤治疗的靶向双室纳米颗粒的系统递送
- 批准号:
10584553 - 财政年份:2022
- 资助金额:
$ 42.9万 - 项目类别:
Uncover the role of H3.3-G343R mutation in shaping the DNA damage response, anti-tumor immunity and mechanisms of resistance in glioma.
揭示 H3.3-G343R 突变在塑造神经胶质瘤 DNA 损伤反应、抗肿瘤免疫和耐药机制中的作用。
- 批准号:
10384185 - 财政年份:2022
- 资助金额:
$ 42.9万 - 项目类别:
Uncover the role of H3.3-G343R mutation in shaping the DNA damage response, anti-tumor immunity and mechanisms of resistance in glioma.
揭示 H3.3-G343R 突变在塑造神经胶质瘤 DNA 损伤反应、抗肿瘤免疫和耐药机制中的作用。
- 批准号:
10550245 - 财政年份:2022
- 资助金额:
$ 42.9万 - 项目类别:
Systemic Delivery of Targeted Bi-Compartmental Nanoparticles for Glioblastoma Therapeutics
用于胶质母细胞瘤治疗的靶向双室纳米颗粒的系统递送
- 批准号:
10462033 - 财政年份:2022
- 资助金额:
$ 42.9万 - 项目类别:
Novel nano-vaccine technology for inducing immunity against gliomas
用于诱导神经胶质瘤免疫力的新型纳米疫苗技术
- 批准号:
10443896 - 财政年份:2021
- 资助金额:
$ 42.9万 - 项目类别:
Novel nano-vaccine technology for inducing immunity against gliomas
用于诱导神经胶质瘤免疫力的新型纳米疫苗技术
- 批准号:
10655464 - 财政年份:2021
- 资助金额:
$ 42.9万 - 项目类别:
Administrative Diversity Supplement- Novel Nano-Vaccine Technology for Inducing Immunity Against Gliomas
行政多样性补充-诱导神经胶质瘤免疫的新型纳米疫苗技术
- 批准号:
10622660 - 财政年份:2021
- 资助金额:
$ 42.9万 - 项目类别:
Novel nano-vaccine technology for inducing immunity against gliomas
用于诱导神经胶质瘤免疫力的新型纳米疫苗技术
- 批准号:
10877283 - 财政年份:2021
- 资助金额:
$ 42.9万 - 项目类别:
Novel nano-vaccine technology for inducing immunity against gliomas
用于诱导神经胶质瘤免疫力的新型纳米疫苗技术
- 批准号:
10241830 - 财政年份:2021
- 资助金额:
$ 42.9万 - 项目类别:
Immune-suppressive Myeloid Cells in the Glioma Microenvironment: Signaling Mechanisms and Novel Therapeutic Strategies
胶质瘤微环境中的免疫抑制骨髓细胞:信号传导机制和新的治疗策略
- 批准号:
9981837 - 财政年份:2015
- 资助金额:
$ 42.9万 - 项目类别:
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