Data from Chondroitinase ABC I–Mediated Enhancement of Oncolytic Virus Spread and Antitumor Efficacy

Abstract

<div>Abstract<p><b>Purpose:</b> The inhibitory role of secreted chondroitin sulfate proteoglycans on oncolytic viral (OV) therapy was examined. Chondroitinase ABC (Chase-ABC) is a bacterial enzyme that can remove chondroitin sulfate glycosaminoglycans from proteoglycans without any deleterious effects <i>in vivo</i>. We examined the effect of Chase-ABC on OV spread and efficacy.</p><p><b>Experimental Design:</b> Three-dimensional glioma spheroids placed on cultured brain slices were utilized to evaluate OV spread. Replication-conditional OV-expressing Chase-ABC (OV-Chase) was engineered using HSQuik technology and tested for spread and efficacy in glioma spheroids. Subcutaneous and intracranial glioma xenografts were utilized to compare antitumor efficacy of OV-Chase, rHsvQ (control), and PBS. Titration of viral particles was performed from OV-treated subcutaneous tumors. Glioma invasion was assessed in collagen-embedded glioma spheroids <i>in vitro</i> and in intracranial tumors. All statistical tests were two sided.</p><p><b>Results:</b> Treatment with Chase-ABC in cultured glioma cells significantly enhanced OV spread in glioma spheroids grown on brain slices (<i>P</i> < 0.0001). Inoculation of subcutaneous glioma xenografts with Chase-expressing OV significantly increased viral titer (>10 times, <i>P</i> = 0.0008), inhibited tumor growth, and significantly increased overall animal survival (<i>P</i> < 0.006) compared with treatment with parental rHsvQ virus. Single OV-Chase administration in intracranial xenografts also resulted in longer median survival of animals than rHsvQ treatment (32 vs. 21 days, <i>P</i> < 0.018). Glioma cell migration and invasion were not increased by OV-Chase treatment.</p><p><b>Conclusions:</b> We conclude that degradation of glioma extracellular matrix with OV-expressing bacterial Chase-ABC enhanced OV spread and antitumor efficacy. <i>Clin Cancer Res; 17(6); 1362–72. ©2010 AACR</i>.</p></div>