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：
Richard J. Price
金额：
$ 42.01万
依托单位：
UNIVERSITY OF VIRGINIA
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：
https://reporter.nih.gov/project-details/10041000
关键词：
Absorbable Implants Accounting Affect Aftercare Anti-CD47 Antigen-Presenting Cells Attention Blood Blood - brain barrier anatomy Blood Circulation Brain Brain Neoplasms Bypass CD47 gene CD8-Positive T-Lymphocytes Cells Cessation of life Clinic Clinical Clinical Trials Complex Convection Couples Data Diagnosis Dose Drug Delivery Systems Eating Exposure to Flow Cytometry Focused Ultrasound Frequencies Funding Glioblastoma Glioma Growth Histology Human Image Immune response ImmunoPET Immunocompetent Immunoglobulin G Immunohistochemistry Immunotherapeutic agent Immunotherapy Infiltration Interferon Type II Investigational Therapies Kinetics Life Expectancy Magnetic Resonance Imaging Malignant - descriptor Measurement Mediating Microbubbles Modeling Monoclonal Antibodies Mus Nature Neoplasms Operative Surgical Procedures Patients Penetration Phagocytes Phagocytosis Pharmaceutical Preparations Positioning Attribute Primary Brain Neoplasms Publishing Radiation therapy Regimen Reporting Reproducibility Safety Signal Transduction Signaling Molecule Surface System Technology Testing Therapeutic Time Translating Translations Treatment Efficacy Tumor Antigens astrogliosis brain tissue cancer cell chemotherapy clinical translation image guided image-guided drug delivery improved interstitial neoplastic cell passive transport pre-clinical pressure success targeted imaging targeted treatment temozolomide tumor tumor growth uptake

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.

神经胶质瘤是最常见的恶性人类脑肿瘤，这是大多数死亡原发性脑肿瘤。即使接受手术，放疗和化学疗法治疗， IV胶质母细胞瘤（GB）的预期寿命仅为14个月。治疗GB的主要挑战是它的高度侵入性的性质，因为浸润性癌细胞受到“保护” 和血脑屏障（BBB）的免疫疗法。为了克服这种药物输送障碍的物理障碍，我们通过激活MRI引导的激活血管内微泡（MB）非侵入性开放BBB 超声（FUS）。在此提案中，我们将利用这种非侵入性方法提供抗CD47免疫疗法（MCD47）到神经胶质瘤。 CD47是由癌细胞表达的表面分子，它发送了所谓的“不要吃我” 向吞噬细胞发出信号，最近引起了广泛的关注，因为功能阻止CD47 引发许多肿瘤，包括原发性脑肿瘤。我们的建议有2个具体目标。在AIM 1中，我们将通过使用89ZR-Immunopet来确定成像，FUS应用在药物给药方面的时间和测序如何影响MCD47 传递到GL261神经胶质瘤。用FUS和MB开口的BBB非常复杂，有几个因素可能影响mAb递送（例如，肿瘤间质压的时间变化调节，主动转运与被动转运，并改变了外排转运蛋白表达水平）。那是有很大的理由来确定 FU相对于药物的时间和测序会影响MCD47的输送。接下来，目标2 当使用最多的情况下，将研究MCD47对神经胶质瘤的实验治疗效率 AIM 1中确定的有效时间和测序方案。我们将评估FUS改进的能力 MCD47在控制GL261肿瘤生长，阻断浸润和提高存活方面的效率。可重复性将使用CT-2A神经瘤模型对其进行测试，该模型也既高渗透率又对MCD47进行了反应。到2019年中，全球数十名患者已接受了FUS和MB的治疗，以引起BBB开放，因此，已经为该技术的翻译设定了明确的先例。 UVA容纳低频临床MR 专门用于此应用的图像引导的FUS系统（Insightec Exablate Neuro），我们是为使用FUS和MB的GB患者在BBB跨BBB的药物递送的首次临床试验做准备。那，如果我们能够证明MCD47与FUS和MBS结合使用的治疗效率，我们是位置异常良好，可以快速将这些发现转化为诊所。

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：
Theranostics
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：
Arteriosclerosis, thrombosis, and vascular biology
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.