Martinez-Quintanilla Jordi, He Derek, Wakimoto Hiroaki, Alemany Ramon, Shah Khalid
1] Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
1] Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [3] Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Mol Ther. 2015 Jan;23(1):108-18. doi: 10.1038/mt.2014.204. Epub 2014 Oct 29.
Despite the proven safety of oncolytic viruses (OV) in clinical trials for glioblastoma (GBM), their efficacy has been hindered by suboptimal spreading within the tumor. We show that hyaluronan or hyaluronic acid (HA), an important component of extracellular matrix (ECM), is highly expressed in a majority of tumor xenografts established from patient-derived GBM lines that present both invasive and nodular phenotypes. Intratumoral injection of a conditionally replicating adenovirus expressing soluble hyaluronidase (ICOVIR17) into nodular GBM, mediated HA degradation and enhanced viral spread, resulting in a significant antitumor effect and mice survival. In an effort to translate OV-based therapeutics into clinical settings, we encapsulated human adipose-derived mesenchymal stem cells (MSC) loaded with ICOVIR17 in biocompatible synthetic extracellular matrix (sECM) and tested their efficacy in a clinically relevant mouse model of GBM resection. Compared with direct injection of ICOVIR17, sECM-MSC loaded with ICOVIR17 resulted in a significant decrease in tumor regrowth and increased mice survival. This is the first report of its kind revealing the expression of HA in GBM and the role of OV-mediated HA targeting in clinically relevant mouse model of GBM resection and thus has clinical implications.
尽管溶瘤病毒（OV）在胶质母细胞瘤（GBM）的临床试验中已被证明具有安全性，但其疗效却因在肿瘤内的扩散不理想而受到阻碍。我们发现，透明质酸（HA）作为细胞外基质（ECM）的重要组成部分，在大多数源自呈现侵袭性和结节性表型的患者GBM细胞系的肿瘤异种移植中高表达。向结节性GBM瘤内注射表达可溶性透明质酸酶的条件性复制腺病毒（ICOVIR17），可介导HA降解并增强病毒扩散，从而产生显著的抗肿瘤作用并延长小鼠存活时间。为了将基于OV的治疗方法转化为临床应用，我们将负载ICOVIR17的人脂肪来源间充质干细胞（MSC）封装在生物相容性合成细胞外基质（sECM）中，并在GBM切除的临床相关小鼠模型中测试其疗效。与直接注射ICOVIR17相比，负载ICOVIR17的sECM-MSC可显著降低肿瘤再生并提高小鼠存活率。这是同类研究中首次揭示HA在GBM中的表达以及OV介导的HA靶向在GBM切除临床相关小鼠模型中的作用，因此具有临床意义。
