ImmunoPET Assessment of anti-CD47 Immunotherapy Delivery to Glioblastoma with Focused Ultrasound
使用聚焦超声对胶质母细胞瘤进行抗 CD47 免疫治疗的免疫PET评估
基本信息
- 批准号:10041000
- 负责人:
- 金额:$ 42.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-01 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:Absorbable ImplantsAccountingAffectAftercareAnti-CD47Antigen-Presenting CellsAttentionBloodBlood - brain barrier anatomyBlood CirculationBrainBrain NeoplasmsBypassCD47 geneCD8-Positive T-LymphocytesCellsCessation of lifeClinicClinicalClinical TrialsComplexConvectionCouplesDataDiagnosisDoseDrug Delivery SystemsEatingExposure toFlow CytometryFocused UltrasoundFrequenciesFundingGlioblastomaGliomaGrowthHistologyHumanImageImmune responseImmunoPETImmunocompetentImmunoglobulin GImmunohistochemistryImmunotherapeutic agentImmunotherapyInfiltrationInterferon Type IIInvestigational TherapiesKineticsLife ExpectancyMagnetic Resonance ImagingMalignant - descriptorMeasurementMediatingMicrobubblesModelingMonoclonal AntibodiesMusNatureNeoplasmsOperative Surgical ProceduresPatientsPenetrationPhagocytesPhagocytosisPharmaceutical PreparationsPositioning AttributePrimary Brain NeoplasmsPublishingRadiation therapyRegimenReportingReproducibilitySafetySignal TransductionSignaling MoleculeSurfaceSystemTechnologyTestingTherapeuticTimeTranslatingTranslationsTreatment EfficacyTumor Antigensastrogliosisbrain tissuecancer cellchemotherapyclinical translationimage guidedimage-guided drug deliveryimprovedinterstitialneoplastic cellpassive transportpre-clinicalpressuresuccesstargeted imagingtargeted treatmenttemozolomidetumortumor growthuptake
项目摘要
Gliomas are the most common malignant human brain tumors, accounting for the majority of deaths from
primary brain neoplasms. Even when treated with surgery, radiotherapy, and chemotherapy, patients with grade
IV glioblastoma (GB) have a life expectancy of only 14 months. A major challenge to treating GB is its highly
invasive nature, as infiltrating cancer cells are “protected” from exposure to systemically administered chemo-
and immunotherapies by the blood brain barrier (BBB). To overcome this physical this barrier to drug delivery,
we non-invasively open the BBB via the activation of intravascular microbubbles (MBs) with MRI-guided focused
ultrasound (FUS). In this proposal, we will utilize this non-invasive approach to deliver anti-CD47 immunotherapy
(mCD47) to gliomas. CD47, a surface molecule expressed by cancer cells that sends a so-called “don’t eat me”
signal to phagocytic cells, has garnered considerable attention recently because functionally blocking CD47
elicits control of many neoplasms, including primary brain tumors.
Our proposal has 2 specific aims. In Aim 1, we will determine, through the use of 89Zr-ImmunoPET
imaging, how the timing and sequencing of FUS application with respect to drug administration affects mCD47
delivery to GL261 gliomas. BBB opening with FUS and MBs is extremely complex, with several factors potentially
influencing mAb delivery (e.g. time-varying modulation of tumor interstitial pressure, active vs. passive transport,
and altered efflux transporter expression levels). Thus, there is strong rationale to definitively establish how the
timing and sequencing of FUS with respect to drug administration affects the delivery of mCD47. Next, Aim 2
will investigate the experimental therapeutic efficacy of mCD47 against gliomas when delivered using the most
effective timing and sequencing regimen identified in Aim 1. We will evaluate the ability of FUS to improve
mCD47 efficacy in controlling GL261 tumor growth, blocking infiltration, and improving survival. Reproducibility
will be tested using the CT-2A glioma model, which is also both highly infiltrative and responsive to mCD47.
By mid-2019, dozens of patients worldwide had been treated with FUS and MBs to elicit BBB opening,
thus a clear precedent has been set for translation of this technology. UVa houses a low-frequency clinical MR
image-guided FUS system (Insightec Exablate Neuro) that is specialized for this application, and we are
preparing for our first clinical trial for drug delivery across the BBB in GB patients using FUS and MBs. Thus, if
we are able to demonstrate therapeutic efficacy of mCD47 in combination with FUS and MBs, we are
exceptionally well-positioned to rapidly translate these findings to the clinic.
胶质瘤是人类最常见的恶性脑瘤,占死亡人数的大部分。
原发脑肿瘤。即使在接受手术、放射治疗和化疗时,
IV型胶质母细胞瘤(GB)的预期寿命只有14个月。对待英国的一个主要挑战是它的高度
侵袭性,因为浸润性癌细胞受到保护,不会受到全身化疗的影响。
以及通过血脑屏障(BBB)进行免疫治疗。为了克服这种物理障碍,这种药物输送的障碍,
我们通过在MRI引导下聚焦激活血管内微泡(MBS)来非侵入性地打开血脑屏障
超声波(FUS)。在这项提议中,我们将利用这种非侵入性的方法来提供抗CD47免疫治疗。
(MCD47)到胶质瘤。CD47是一种由癌细胞表达的表面分子,它发出所谓的“不要吃我”
信号传导到吞噬细胞,最近引起了相当大的关注,因为功能上阻止了CD47
可控制许多肿瘤,包括原发脑瘤。
我们的建议有两个具体目标。在目标1中,我们将通过使用89Zr-免疫PET来确定
关于给药的FUS应用的时间和顺序如何影响mCD47的成像
向GL261胶质瘤投递。用FUS和MBS开启BBB是极其复杂的,可能有几个因素
影响单抗递送(例如,肿瘤间质压力的时变调制,主动与被动转运,
和改变的外排转运体表达水平)。因此,有充分的理由明确地确定
与给药有关的FUS的时间和序列影响mCD47的传递。接下来,目标2
将研究mCD47在使用大多数情况下对胶质瘤的实验性治疗效果
目标1中确定的有效计时和排序方案。我们将评估FUS的改进能力
MCD47具有抑制GL261肿瘤生长、阻断肿瘤侵袭、提高生存率的作用。可再现性
将使用CT-2A胶质瘤模型进行测试,该模型也是高度浸润性的,对mCD47有反应。
到2019年年中,全球已有数十名患者接受了FUS和MBS治疗,以诱导BBB开放,
因此,这项技术的翻译开创了一个明确的先例。UVA拥有一台低频临床磁共振
图像引导FUS系统(InSightec ExAblate Neuro)专门用于此应用程序,我们
准备我们的第一个临床试验,在使用FUS和MBS的GB患者中跨血脑屏障给药。因此,如果
我们能够展示mCD47与FUS和MBS的联合治疗效果,我们是
处于非常有利的地位,能够迅速将这些发现转化为临床。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Multiple regression analysis of a comprehensive transcriptomic data assembly elucidates mechanically- and biochemically-driven responses to focused ultrasound blood-brain barrier disruption.
- DOI:10.7150/thno.65064
- 发表时间:2021
- 期刊:
- 影响因子:12.4
- 作者:Mathew AS;Gorick CM;Price RJ
- 通讯作者:Price RJ
Magnetic Resonance Imaging of Mouse Cerebral Cavernomas Reveal Differential Lesion Progression and Variable Permeability to Gadolinium.
小鼠脑海绵状血管瘤的磁共振成像揭示了不同的病变进展和对钆的可变渗透性。
- DOI:10.1161/atvbaha.122.318938
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Fisher,DelaneyG;Sharifi,KhadijehA;Ulutas,EZeynep;Kumar,JeyanS;Kalani,MYasharS;Miller,GWilson;Price,RichardJ;Tvrdik,Petr
- 通讯作者:Tvrdik,Petr
Computational model of brain endothelial cell signaling pathways predicts therapeutic targets for cerebral pathologies.
- DOI:10.1016/j.yjmcc.2021.11.005
- 发表时间:2022-03
- 期刊:
- 影响因子:5
- 作者:Gorick CM;Saucerman JJ;Price RJ
- 通讯作者:Price RJ
Applications of focused ultrasound-mediated blood-brain barrier opening.
- DOI:10.1016/j.addr.2022.114583
- 发表时间:2022-12
- 期刊:
- 影响因子:16.1
- 作者:
- 通讯作者:
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Richard J. Price其他文献
A novel ‘bottom-up’ synthesis of few- and multi-layer graphene platelets with partial oxidation via cavitation
- DOI:
10.1016/j.ultsonch.2019.03.020 - 发表时间:
2019-09-01 - 期刊:
- 影响因子:
- 作者:
Richard J. Price;Paul I. Ladislaus;Graham C. Smith;Trevor J. Davies - 通讯作者:
Trevor J. Davies
Dynamics of Adult Axin2 Cell Lineage Integration in Granule Neurons of the Dentate Gyrus
齿状回颗粒神经元中成人 Axin2 细胞谱系整合的动态
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:0
- 作者:
Khadijeh A. Sharifi;Faraz Farzad;Sauson Soldozy;Richard J. Price;M. Y. S. Kalani;P. Tvrdik - 通讯作者:
P. Tvrdik
Focused ultrasound augments the delivery and penetration of model therapeutics into cerebral cavernous malformations
聚焦超声增强了模型治疗药物向脑海绵状血管畸形的递送和渗透。
- DOI:
10.1016/j.jconrel.2025.113861 - 发表时间:
2025-07-10 - 期刊:
- 影响因子:11.500
- 作者:
Delaney G. Fisher;Matthew R. Hoch;Catherine M. Gorick;Claire Huchthausen;Victoria R. Breza;Khadijeh A. Sharifi;Petr Tvrdik;G. Wilson Miller;Richard J. Price - 通讯作者:
Richard J. Price
Focused ultrasound-microbubble treatment arrests the growth and formation of cerebral cavernous malformations
聚焦超声微泡治疗可阻止脑海绵状畸形的生长和形成
- DOI:
10.1038/s41551-025-01390-z - 发表时间:
2025-05-13 - 期刊:
- 影响因子:26.600
- 作者:
Delaney G. Fisher;Tanya Cruz;Matthew R. Hoch;Khadijeh A. Sharifi;Ishaan M. Shah;Catherine M. Gorick;Victoria R. Breza;Anna C. Debski;Joshua D. Samuels;Jason P. Sheehan;David Schlesinger;David Moore;James W. Mandell;John R. Lukens;G. Wilson Miller;Petr Tvrdik;Richard J. Price - 通讯作者:
Richard J. Price
Richard J. Price的其他文献
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{{ truncateString('Richard J. Price', 18)}}的其他基金
Genome Editing the Blood-Brain Barrier with Sonoselective Focused Ultrasound
利用声选择性聚焦超声对血脑屏障进行基因组编辑
- 批准号:
10403487 - 财政年份:2021
- 资助金额:
$ 42.01万 - 项目类别:
Genome Editing the Blood-Brain Barrier with Sonoselective Focused Ultrasound
利用声选择性聚焦超声对血脑屏障进行基因组编辑
- 批准号:
10554403 - 财政年份:2021
- 资助金额:
$ 42.01万 - 项目类别:
Innovative systemic gene therapy for treating Parkinson's disease
治疗帕金森病的创新系统基因疗法
- 批准号:
10164880 - 财政年份:2019
- 资助金额:
$ 42.01万 - 项目类别:
Innovative systemic gene therapy for treating Parkinson's disease
治疗帕金森病的创新系统基因疗法
- 批准号:
9927696 - 财政年份:2019
- 资助金额:
$ 42.01万 - 项目类别:
Innovative systemic gene therapy for treating Parkinson's disease
治疗帕金森病的创新系统基因疗法
- 批准号:
10394379 - 财政年份:2019
- 资助金额:
$ 42.01万 - 项目类别:
Innovative systemic gene therapy for treating Parkinson's disease
治疗帕金森病的创新系统基因疗法
- 批准号:
10609832 - 财政年份:2019
- 资助金额:
$ 42.01万 - 项目类别:
Endothelial DNA Methylation, Arteriogenic Capacity, and Shear Stress "Set-Point."
内皮 DNA 甲基化、动脉生成能力和剪切应力“设定点”。
- 批准号:
9311466 - 财政年份:2017
- 资助金额:
$ 42.01万 - 项目类别:
Application of Laser Speckle Flowmetry to Vascular Remodeling
激光散斑流量计在血管重塑中的应用
- 批准号:
8765491 - 财政年份:2014
- 资助金额:
$ 42.01万 - 项目类别:
Application of Laser Speckle Flowmetry to Vascular Remodeling
激光散斑流量计在血管重塑中的应用
- 批准号:
8887112 - 财政年份:2014
- 资助金额:
$ 42.01万 - 项目类别:
Bevacizumab Delivery to Glioblastoma with MR-Guided Focused Ultrasound
通过 MR 引导聚焦超声将贝伐珠单抗递送至胶质母细胞瘤
- 批准号:
8628120 - 财政年份:2013
- 资助金额:
$ 42.01万 - 项目类别:
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