*5.2. Arming with Matrix-Modifying Genes to Enhance Intratumoral Virus Spreading*

Tumor cells are embedded in a dense network of extracellular matrix (ECM) and infection-resistant stroma cells, which impair effective distribution of the virus. To address this issue, oAds have been provided with matrix modifying genes such as TIMP2, TIMP3, MMP8, and relaxin. Expression of these matrix modifiers enhanced intratumoral viral spread and effectively inhibited tumor growth in cancer xenograft models in mice [70–73].

VCN-01, a clinically investigated oAd (see above), is armed with a soluble human sperm hyaluronidase (PH-20), which effectively degrades hyaluronan. Degradation of the ECM by PH-20 results in enhanced virus spreading in xenografted tumors [56]. Mutants of the proteoglycan decorin have been used to improve viral distribution and tumor penetration by oAds [74]. In the future, it will be interesting to see how degradation of the ECM can promote leukocyte infiltration and immune activation of the tumor microenvironment. Recently, it has been shown with a relaxin-expressing oAd that the ECM degradation enhanced tumor penetration by a systemically administered therapeutic antibody. When oAds additionally expressed IL-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF), tumors were effectively converted into an immunoactivated state responsive to PD-1 checkpoint inhibition [75].
