ImmunoPET Assessment of anti-CD47 Immunotherapy Delivery to Glioblastoma with Focused Ultrasound

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。

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.