Oncolytic viral vectors show enormous potential for the treatment of many solid
tumors. However, these vectors often suffer from insufficient delivery within
tumors, which limits their efficacy in both preclinical and clinical settings. We have previously shown that
tumor collagen can significantly hinder diffusion, and that its degradation can enhance the distribution and efficacy of an oncolytic herpes simplex virus (HSV) vector. Here, we identify two members of the
matrix metalloproteinase (
MMP) family of
enzymes, MMP-1 and MMP-8, which can modulate the
tumor matrix and enhance HSV delivery and efficacy. We show that overexpression of MMP-1 and MMP-8 in the human
soft tissue sarcoma HSTS26T leads to a significant depletion of
tumor-sulfated
glycosaminoglycans. This increases the hydraulic conductivity of these
tumors and enhances the flow of virus during injection. In control
tumors, injected virus accumulates primarily in the periphery of the
tumor. In contrast, we observed a more widespread distribution of virus around the injection site in MMP-1- and MMP-8-expressing
tumors. Due to this enhanced vector delivery,
MMP-expressing
tumors respond significantly better to oncolytic HSV treatment than control
tumors. Thus, these findings introduce a new approach to improve the delivery and efficacy of oncolytic viral vectors: modulation of
tumor glycosaminoglycans to enhance convection.