Early treatment of HER2-amplified brain tumors with targeted NK-92 cells and focused ultrasound improves survival
Early treatment of HER2-amplified brain tumors with targeted NK-92 cells and focused ultrasound improves survival
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DOI：
10.1093/neuonc/nov318
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发表时间：
2016-07-01
期刊：
影响因子：
15.9
通讯作者：
Hynynen, Kullervo
中科院分区：
文献类型：
--
作者：
Alkins, Ryan;Burgess, Alison;Hynynen, Kullervo
背景恶性脑肿瘤的预后很差，手术后残留的肿瘤需要辅助放化疗。血脑屏障阻碍许多化疗药物，导致适度的治疗效果。我们以前证明，靶向自然杀伤（NK）-92细胞可以使用MRI引导的聚焦超声和去甲肾上腺素微泡递送到大脑的所需区域。靶向NK-92细胞具有优于许多全身性疗法的优点，包括其对恶性细胞（特别是表达靶抗原的那些细胞）的特异性细胞毒性、保留健康细胞的能力以及不受外排通道的影响。我们研究了靶向NK-92细胞、聚焦超声和微泡的纵向治疗是否可以减缓肿瘤生长并提高原位HER 2扩增啮齿动物脑肿瘤模型的生存率，该模型使用人乳腺癌细胞系作为原型。HER 2受体参与细胞生长和分化，在原发性和转移性脑肿瘤中都有表达。HER 2扩增的乳腺癌有较高的中枢神经系统转移风险和较差的预后。与每两周一次的治疗或单独治疗相比，使用靶向NK-92细胞和超声的早期强化治疗改善了生存率。强化治疗模式导致50%的受试者长期生存。许多肿瘤蛋白可以用于NK-92细胞系的靶向治疗;结合经颅超声的安全性证据，这些结果可能很快就可以转化为脑肿瘤患者的高度靶向治疗选择。
Background. Malignant brain tumors have a dismal prognosis, with residual tumor remaining after surgery necessitating adjuvant chemoradiotherapy. The blood-brain barrier hinders many chemotherapeutic agents, resulting in modest treatment efficacy. We previously demonstrated that targeted natural killer (NK)-92 cells could be delivered to desired regions of the brain using MRI-guided focused ultrasound and Definity microbubbles. Targeted NK-92 cells have advantages over many systemic therapies including their specific cytotoxicity to malignant cells (particularly those expressing the target antigen), ability to spare healthy cells, and being unaffected by efflux channels.Methods. We investigated whether longitudinal treatments with targeted NK-92 cells, focused ultrasound, and microbubbles could slow tumor growth and improve survival in an orthotopic HER2-amplified rodent brain tumor model using a human breast cancer line as a prototype. The HER2 receptor, involved in cell growth and differentiation, is expressed by both primary and metastatic brain tumors. Breast cancers with HER2 amplification have a higher risk of CNS metastasis and poorer prognosis.Results. Early intensive treatment with targeted NK-92 cells and ultrasound improved survival compared with biweekly treatments or either treatment alone. The intensive treatment paradigm resulted in long-term survival in 50% of subjects.Conclusions. Many tumor proteins could be exploited for targeted therapy with the NK-92 cell line; combined with the mounting safety evidence for transcranial ultrasound, these results may soon be translatable to a highly targeted treatment option for patients with brain tumors.