Oncolytic viral
therapy provides a promising approach to treat certain human
malignancies. These vectors improve on replication-deficient vectors by increasing the viral load within
tumors through preferential viral replication within
tumor cells. However, the inability to efficiently propagate throughout the entire
tumor and infect cells distant from the injection site has limited the capacity of oncolytic viruses to achieve consistent therapeutic responses. Here we show that the spread of the oncolytic herpes simplex virus (HSV) vector MGH2 within the human
melanoma Mu89 is limited by the
fibrillar collagen in the extracellular matrix. This limitation seems to be size specific as nanoparticles of equivalent size to the virus distribute within
tumors to the same extent whereas smaller particles distribute more widely. Due to limited viral penetration,
tumor cells in inaccessible regions continue to grow, remaining out of the range of
viral infection, and
tumor eradication cannot be achieved. Matrix modification with bacterial
collagenase coinjection results in a significant improvement in the initial range of viral distribution within the
tumor. This results in an extended range of infected
tumor cells and improved virus propagation, ultimately leading to enhanced therapeutic outcome. Thus,
fibrillar collagen can be a formidable barrier to viral distribution and matrix-modifying treatments can significantly enhance the therapeutic response.