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.

Therapeutically engineered stem cells (SC) are emerging as an effective tumor-targeted approach for different cancer types. However, the assessment of the long-term fate of therapeutic SC post-tumor treatment is critical if such promising therapies are to be translated into clinical practice. In this study, we have developed an efficient stem cell based therapeutic strategy that simultaneously allows killing of tumor cells and assessment and eradication of SC post highly malignant glioblastoma multiforme (GBM) treatment. Mesenchymal stem cells (MSC) engineered to co-express the prodrug converting enzyme, herpes simplex virus thymidine kinase (HSV-TK) and a potent and secretable variant of tumor necrosis factor apoptosis-inducing ligand (S-TRAIL), induced caspase-mediated GBM cell death and showed selective MSC sensitization to the prodrug ganciclovir (GCV). A significant decrease in tumor growth and a subsequent increase in survival were observed when mice bearing highly aggressive GBM were treated with MSC co-expressing S-TRAIL and HSV-TK. Furthermore, the systemic administration of GCV post-tumor treatment selectively eliminated therapeutic MSC expressing HSV-TK in vitro and in vivo, which was monitored in real time by positron emission-computed tomography (PET) imaging utilizing 18F-FHBG, a substrate for HSV-TK. These findings demonstrate the development and validation of a novel therapeutic strategy that has implications in translating stem cell based therapies in cancer patients.