Designing and building oncolytic viruses

Maroun, Justin; Muñoz-Alía, Miguel; Ammayappan, Arun; Schulze, Autumn; Peng, Kah-Whye; Russell, Stephen

Replication and amplification in the tumor is the major feature that sets OVs apart from other anticancer drugs. No traditional chemotherapy, immunotherapy or small molecule inhibitor can target tumor cells and then amplify at the site of action and spread to other sites of tumor growth. Specificity as well as speed and extent of IT virus replication are the key determinants of therapeutic index (efficacy/toxicity ratio) for an OV therapeutic, and each of these parameters can be modified by virus engineering. Additionally, the kinetics of spread can be impacted by combining the virus with immunomodulatory drugs. The idea of a virus with selective tropism for cancerous tissue has obvious appeal. Even for naturally occurring viruses that have not been tropism modified, a tumor offers a favorable environment to support a productive infection, and this is borne out by case reports of temporary remission or regression of different cancers concurrent with viral infections [4, 93] . There are several reasons why tumors are generally more susceptible than normal tissues to virus attack; poorly developed lymphatics, high nonsuppressible metabolic activity, resistance to apoptosis, poor responsiveness to interferon and intrinsic suppression of immune effector cells. But as we move in the direction of intentionally using virus infections to mediate tumor destruction, it is apparent that a targeted virus with exquisite tumor specificity will be superior to its non targeted counterpart, allowing for the administration of higher tumor destructive doses without toxicity to normal tissues.