Engineering Oncolytic Vaccinia Virus to Remodel the Tumor Microenvironment and Improve Efficacy of Combinational Cancer Therapies
Oncolytic viruses (OVs) are promising biotherapeutics that selectively infect and kill cancer cells. The efficacy of oncolytic viral therapy depends on the virus's efficient replication and dissemination within tumors. However, tumors often develop a dense extracellular matrix (ECM) surrounding their cells that provides resistance against many forms of cancer therapies including OVs. To overcome this barrier, we propose encoding OVs with enzymes that degrade the ECM, so that upon infection of cancer cells, the surrounding inhibitory barrier of ECM is broken down and viral spread is improved In addition, the local degradation of the tumor ECM will simultaneously benefit conventional chemo- and immuno-therpies targeting the tumor. The main objective of this proposal will be to identify suitable ECM-degrading enzymes that synergize with OV treatment and to engineer them to be expressed from the virus. These viruses will then serve as a platform to combine with other therapeutic payloads, which will directly benefit their delivery and dissemination throughout the tumor.