Encapsulated Stem Cells Loaded With Hyaluronidase-expressing Oncolytic Virus for Brain Tumor Therapy

Abstract

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.

Expression of Concern: Therapeutic targeting of chemoresistant and recurrent glioblastoma stem cells with a proapoptotic variant of oncolytic herpes simplex virus

“…Extracellular matrix (ECM) within GBM can hamper intratumoral spread of oncolytic viruses by presenting physical barriers . We recently demonstrated that an important component of ECM, hyaluronan, is abundant in GBM and an oncolytic virus expressing hyaluronidase mediates increased intratumoral spread and anti‐GBM potency . Simultaneous expression of TRAIL and hyaluronidase in the context of oHSV might overcome both resistance and delivery problems associated with oHSV therapy of highly invasive GBM.…”

Anti-GD2-ch14.18/CHO coated nanoparticles mediate glioblastoma (GBM)-specific delivery of the aromatase inhibitor, Letrozole, reducing proliferation, migration and chemoresistance in patient-derived GBM tumor cells

“…Such an aggregation causes the nanoparticles to behave like larger particles [58] and may affect systemic delivery for therapeutic application in the brain. However, evaluation of potential therapeutics through direct intratumoral injection including nanoparticle delivery to in vivo models of GBM [59, 60] or at the point of patient tumor resection or biopsy [61–65] in several studies indicates that such systemic transport challenges can be circumvented to facilitate therapeutic delivery in a clinical setting.…”

Genetisch modifizierte Zellen zur Therapie verschiedener Erkrankungen

“…Ein weiterer tumortherapeutischer Ansatz ist die genetische Modifikation von MSCs mit dem Genom für onkolytische Viren [31][32][33]. Solche Viren sind von Natur aus oder durch genetische Modifikation in der Lage, bevorzugt Tumorzellen zu infizieren bzw.…”