Karmur Brij S, Philteos Justine, Abbasian Aram, Zacharia Brad E, Lipsman Nir, Levin Victor, Grossman Stuart, Mansouri Alireza
Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Department of Physiology, University of Toronto, Toronto, ON, Canada.
Front Oncol. 2020 Sep 18;10:563840. doi: 10.3389/fonc.2020.563840. eCollection 2020.
The blood-brain barrier (BBB) presents a formidable challenge in the development of effective therapeutics in neuro-oncology. This has fueled several decades of efforts to develop strategies for disrupting the BBB, but progress has not been satisfactory. As such, numerous drug- and device-based methods are currently being investigated in humans. Through a focused assessment of completed, active, and pending clinical trials, our first aim in this review is to outline the scientific foundation, successes, and limitations of the BBBD strategies developed to date. Among 35 registered trials relevant to BBBD in neuro-oncology in the ClinicalTrials.gov database, mannitol was the most common drug-based method, followed by RMP-7 and regadenoson. MR-guided focused ultrasound was the most common device-based method, followed by MR-guided laser ablation, ultrasound, and transcranial magnetic stimulation. While most early-phase studies focusing on safety and tolerability have met stated objectives, advanced-phase studies focusing on survival differences and objective tumor response have been limited by heterogeneous populations and tumors, along with a lack of control arms. Based on shared challenges among all methods, our second objective is to discuss strategies for confirmation of BBBD, choice of systemic agent and drug design, alignment of BBBD method with real-world clinical workflow, and consideration of inadvertent toxicity associated with disrupting an evolutionarily-refined barrier. Finally, we conclude with a strategic proposal to approach future studies assessing BBBD.
血脑屏障（BBB）在神经肿瘤学有效治疗方法的开发中构成了巨大挑战。这推动了数十年来为开发破坏血脑屏障的策略所做的努力，但进展并不令人满意。因此，目前正在对多种基于药物和设备的方法进行人体研究。通过对已完成、正在进行和即将开展的临床试验进行重点评估，我们撰写本综述的首要目标是概述迄今为止所开发的血脑屏障破坏（BBBD）策略的科学基础、成功之处和局限性。在ClinicalTrials.gov数据库中与神经肿瘤学BBBD相关的35项注册试验中，甘露醇是最常用的基于药物的方法，其次是RMP - 7和瑞加诺生。磁共振引导聚焦超声是最常用的基于设备的方法，其次是磁共振引导激光消融、超声和经颅磁刺激。虽然大多数侧重于安全性和耐受性的早期研究达到了既定目标，但侧重于生存差异和客观肿瘤反应的晚期研究受到人群和肿瘤异质性以及缺乏对照臂的限制。基于所有方法共有的挑战，我们的第二个目标是讨论血脑屏障破坏的确认策略、全身用药的选择和药物设计、血脑屏障破坏方法与实际临床工作流程的匹配，以及对破坏一个经过进化优化的屏障所带来的意外毒性的考虑。最后，我们提出一项战略建议，以指导未来评估血脑屏障破坏的研究。
