Department of Neurological Surgery, University of Southern California, Los Angeles, California, USA.
Department of Neurosurgery, Luzhou, China.
Neuro Oncol. 2021 Oct 1;23(10):1656-1667. doi: 10.1093/neuonc/noab041.
The antitumor efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapies, such as humanized monoclonal antibody trastuzumab (Herceptin®, Roche), in patients with breast-to-brain cancer metastasis is hindered by the low permeability of the blood-brain barrier (BBB). NEO100 is a high-purity version of the natural monoterpene perillyl alcohol, produced under current good manufacturing practice (cGMP) regulations, that was shown previously to reversibly open the BBB in rodent models. Here we investigated whether NEO100 could enable brain entry of trastuzumab to achieve greater therapeutic activity.
An in vitro BBB, consisting of human astrocytes and brain endothelial cells, was used to determine trastuzumab penetration in the presence or absence of NEO100. For in vivo studies, we administered intravenous (IV) trastuzumab or the trastuzumab-drug conjugate ado-trastuzumab emtansine (T-DM1; Kadcyla®, Roche), to mouse models harboring intracranial HER2+ breast cancer, with or without BBB opening via IA NEO100. Brain and tumor tissues were examined for the presence of trastuzumab and infiltration of immune cells. Therapeutic impact was evaluated based on overall survival.
NEO100 greatly increased trastuzumab penetration across an in vitro BBB. In vivo, IA NEO100-mediated BBB opening resulted in brain tumor-selective accumulation of trastuzumab, without detectable presence in normal brain tissue, along with increased presence of immune cell populations. IV delivery of trastuzumab or T-DM1 achieved significantly greater overall survival of tumor-bearing mice when combined with IA NEO100.
IA NEO100 facilitates brain tumor entry of trastuzumab and T-DM1 and significantly enhances their therapeutic efficacy, along with increased antibody-dependent immune cell recruitment.
曲妥珠单抗（赫赛汀®，罗氏）等针对人表皮生长因子受体 2（HER2）的抗肿瘤疗效在乳腺癌脑转移患者中受到血脑屏障（BBB）通透性低的阻碍。NEO100 是一种高纯度天然单萜化合物紫苏醇，在现行良好生产规范（cGMP）法规下生产，先前已证明可在啮齿动物模型中可逆地打开 BBB。在这里，我们研究了 NEO100 是否可以使曲妥珠单抗进入大脑，以实现更大的治疗活性。
使用由人星形胶质细胞和脑内皮细胞组成的体外 BBB 来确定存在或不存在 NEO100 时曲妥珠单抗的渗透。对于体内研究，我们向携带颅内 HER2+乳腺癌的小鼠模型静脉内（IV）给予曲妥珠单抗或曲妥珠单抗-药物偶联物 ado-trastuzumab emtansine（T-DM1；Kadcyla®，罗氏），通过 IA NEO100 打开 BBB 或不打开 BBB。检查脑和肿瘤组织中曲妥珠单抗的存在和免疫细胞的浸润。根据总生存期评估治疗效果。
NEO100 大大增加了曲妥珠单抗在体外 BBB 中的渗透。在体内，IA NEO100 介导的 BBB 打开导致曲妥珠单抗在脑肿瘤中选择性积累，而在正常脑组织中未检测到，同时免疫细胞群体增加。当与 IA NEO100 联合使用时，IV 给予曲妥珠单抗或 T-DM1 可显著延长荷瘤小鼠的总生存期。
IA NEO100 促进曲妥珠单抗和 T-DM1 进入脑肿瘤，并显著增强其治疗效果，同时增加抗体依赖性免疫细胞募集。
