Sunnybrook Research Institute, Harquail Centre for Neuromodulation, Toronto, ON M4N 3M5, Canada.
Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON M5S 1A4, Canada.
Sci Transl Med. 2021 Oct 13;13(615):eabj4011. doi: 10.1126/scitranslmed.abj4011.
The blood-brain barrier (BBB) is an important factor limiting the effectiveness of central nervous system (CNS) therapeutics. MR-guided focused ultrasound (MRgFUS) is a noninvasive, spatially precise technology that enhances drug delivery across a temporarily permeable BBB. However, despite promising preclinical data, successful drug delivery has yet to be proven in human patients. In this study, we provide primary evidence of enhanced brain penetration of trastuzumab with MRgFUS in patients with Her2-positive breast cancer and brain metastases (NCT03714243). Four patients with progressive intracranial disease and stable systemic disease were enrolled in a single-arm open-labeled study. Twenty treatments combining transcranial MRgFUS with concomitant standard-of-care intravenous trastuzumab-based therapies were administered as outpatient procedures. The primary outcome was safety, and there were no treatment-related serious adverse events. The efficacy of trastuzumab delivery was demonstrated using In-BzDTPA-NLS-trastuzumab SPECT imaging. The standardized uptake value ratio (SUVR) of MRgFUS-treated lesions increased, on average, by 101 ± 71%, compared to −18 ± 26% in control lesions. MRgFUS enhanced drug uptake in 87 ± 17% of sonicated voxels (>20% increase in SUVR), with up to a 450% voxel-wise increase detected. Control lesions had 8 ± 8% voxels with >20% increase in SUVR. With treatment, unidimensional tumor measurements decreased by 19 ± 12%. This study provides first-in-human evidence of noninvasive, spatially targeted monoclonal antibody delivery across the BBB using MRgFUS, demonstrating the promise of this technology for a broad range of CNS diseases.
血脑屏障（BBB）是限制中枢神经系统（CNS）治疗效果的重要因素。MR 引导聚焦超声（MRgFUS）是一种非侵入性、空间精确的技术，可增强暂时通透性 BBB 下的药物输送。然而，尽管有有前景的临床前数据，但在人类患者中尚未证明成功的药物输送。在这项研究中，我们提供了使用 MRgFUS 在 Her2 阳性乳腺癌和脑转移患者中增强曲妥珠单抗脑穿透的初步证据（NCT03714243）。四名患有进行性颅内疾病和稳定全身疾病的患者被纳入一项单臂开放标签研究。作为门诊程序，共进行了 20 次将经颅 MRgFUS 与同时进行的标准护理基于曲妥珠单抗的静脉治疗相结合的治疗。主要结果是安全性，没有与治疗相关的严重不良事件。使用 In-BzDTPA-NLS-trastuzumab SPECT 成像来证明曲妥珠单抗递送的疗效。与对照病变相比，MRgFUS 治疗病变的标准化摄取值比（SUVR）平均增加 101 ± 71%，而对照病变则为-18 ± 26%。MRgFUS 在 87 ± 17%的超声病变中增强了药物摄取，高达 450%的体素检测到了增加。对照病变中有 8 ± 8%的体素 SUVR 增加超过 20%。经过治疗，一维肿瘤测量值减少了 19 ± 12%。这项研究提供了使用 MRgFUS 无创、空间靶向单克隆抗体穿过 BBB 的人体首次证据，证明了这项技术在广泛的 CNS 疾病中的应用前景。
