Oncolytic Virus

The therapeutic success of oncolytic viruses and other large anti-cancer agents is severely limited by their poor diffusion and distribution through the tumor interstitial space. We have shown that collagen fibers in the tumor interstitial matrix hinder the diffusion of large molecules and penetration of viral particles. We used relaxin – a small hormone – which stimulates the secretion of matrix metalloproteinases and inhibits collagen synthesis – to improve the diffusion of large molecules in collagen-rich tumors. Multiphoton laser scanning microscopy and second harmonic generation imaging of collagen fibers in living tumors demonstrated that relaxin enhances fibrillar collagen degradation. Bacterial collagenase or mammalian collagenases – matrix metalloproteinase-1 or -8 – can also improve the intratumoral penetration and anti-tumor efficacy of oncolytic viruses. Ongoing and future studies will determine how matrix metalloproteinases and inhibition of collagen synthesis affect the composition and transport in the tumor interstitial space. The narrow spacing between cancer cells is also a major barrier hindering the movement of oncolytic viruses. To bypass the cellular barrier, we tested the hypothesis that void space produced by cancer cell apoptosis improves the initial spread and efficacy of oncolytic herpes-simplex virus (HSV). In mice with mammary tumors, cancer cell apoptosis – induced by doxycycline-regulated expression/activation of caspase-8 or cytotoxic agents – enhanced the viral spread and therapeutic efficacy of oncolytic HSV injected intratumorally. In order to improve the systemic efficacy of oncolytic virotherapy targeted both at primary and metastatic tumors, it is also essential to identify agents (e.g., cytotoxic agents) or strategies that will improve the vascular extravasation and interstitial transport of viruses injected intravenously. We are testing if the targeting of tumor blood vessels, cancer cells, or both improves the extravasation and delivery of viral vectors and large particles, and the anti-tumor efficacy of oncolytic HSV.