Morshed R A, Gutova M, Juliano J, Barish M E, Hawkins-Daarud A, Oganesyan D, Vazgen K, Yang T, Annala A, Ahmed A U, Aboody K S, Swanson K R, Moats R A, Lesniak M S
The Brain Tumor Center, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA.
Department of Neuroscience, City of Hope National Medical Center, Beckman Research Institute, Duarte, CA, USA.
Cancer Gene Ther. 2015 Jan;22(1):55-61. doi: 10.1038/cgt.2014.72. Epub 2014 Dec 19.
In preclinical studies, neural stem cell (NSC)-based delivery of oncolytic virus has shown great promise in the treatment of malignant glioma. Ensuring the success of this therapy will require critical evaluation of the spatial distribution of virus after NSC transplantation. In this study, the patient-derived GBM43 human glioma line was established in the brain of athymic nude mice, followed by the administration of NSCs loaded with conditionally replicating oncolytic adenovirus (NSC-CRAd-S-pk7). We determined the tumor coverage potential of oncolytic adenovirus by examining NSC distribution using magnetic resonance (MR) imaging and by three-dimensional reconstruction from ex vivo tissue specimens. We demonstrate that unmodified NSCs and NSC-CRAd-S-pk7 exhibit a similar distribution pattern with most prominent localization occurring at the tumor margins. We were further able to visualize the accumulation of these cells at tumor sites via T2-weighted MR imaging as well as the spread of viral particles using immunofluorescence. Our analyses reveal that a single administration of oncolytic virus-loaded NSCs allows for up to 31% coverage of intracranial tumors. Such results provide valuable insights into the therapeutic potential of this novel viral delivery platform.
在临床前研究中，基于神经干细胞（NSC）递送溶瘤病毒在恶性胶质瘤治疗中显示出巨大潜力。要确保这种疗法的成功，需要对NSC移植后病毒的空间分布进行严格评估。在本研究中，将源自患者的GBM43人胶质瘤细胞系接种到无胸腺裸鼠脑内，随后给予负载有条件复制溶瘤腺病毒的NSC（NSC-CRAd-S-pk7）。我们通过磁共振（MR）成像检查NSC分布以及对离体组织标本进行三维重建，来确定溶瘤腺病毒的肿瘤覆盖潜力。我们证明，未修饰的NSC和NSC-CRAd-S-pk7呈现相似的分布模式，最显著的定位出现在肿瘤边缘。我们还能够通过T2加权MR成像观察到这些细胞在肿瘤部位的聚集，并利用免疫荧光观察到病毒颗粒的扩散。我们的分析表明，单次给予负载溶瘤病毒的NSC可使颅内肿瘤覆盖率高达31%。这些结果为这个新型病毒递送平台的治疗潜力提供了有价值的见解。
