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 ¹¹¹In-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.

中文翻译：

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MR 引导的聚焦超声增强了曲妥珠单抗对 Her2 阳性脑转移瘤的递送

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 引导的聚焦超声 (MRgFUS) 是一种无创、空间精确的技术，可增强药物通过暂时可渗透的 BBB 的输送。然而，尽管有希望的临床前数据，但尚未在人类患者中证明成功的药物输送。在这项研究中，我们提供了曲妥珠单抗与 MRgFUS 增强 Her2 阳性乳腺癌和脑转移患者脑渗透的主要证据 (NCT03714243)。四名患有进行性颅内疾病和稳定的全身性疾病的患者参加了一项单臂开放标签研究。将经颅 MRgFUS 与伴随的基于标准护理的静脉曲妥珠单抗治疗相结合的 20 种治疗作为门诊手术进行。主要结果是安全性，没有与治疗相关的严重不良事件。曲妥珠单抗递送的功效通过使用证明¹¹¹ In-BzDTPA-NLS-曲妥珠单抗 SPECT 成像。MRgFUS 治疗病灶的标准化摄取值比 (SUVR) 平均增加 101 ± 71%，而对照病灶为 -18 ± 26%。MRgFUS 增强了 87 ± 17% 的超声处理体素的药物吸收（SUVR 增加 > 20%），检测到高达 450% 的体素增加。对照病变有 8 ± 8% 的体素，SUVR 增加 > 20%。通过治疗，一维肿瘤测量值减少了 19 ± 12%。这项研究提供了使用 MRgFUS 在 BBB 上进行无创、空间靶向单克隆抗体递送的首次人类证据，证明了该技术对广泛的中枢神经系统疾病的前景。