Oncolytic Virus Combination Therapy: Killing One Bird with Two Stones

Abstract

Over the last 60 years an eclectic collection of microbes has been tested in a variety of pre-clinical models as anti-cancer agents. At the forefront of this research are a number of virus-based platforms that have shown exciting activity in a variety of pre-clinical models and are collectively referred to as oncolytic viruses. Our true understanding of the potential and limitations of this therapeutic modality has been substantially advanced through clinical studies carried out over the last 25 years. Perhaps not surprising, as with all other cancer therapeutics, it has become clear that current oncolytic virus therapeutics on their own are unlikely to be effective in the majority of patients. The greatest therapeutic gains will therefore be made through thoughtful combination strategies built upon an understanding of cancer biology.

Keywords: cancer; combination therapy; immunotherapy; oncolytic virus.

Figure 1

cis versus trans Combination: Advantages and Limitations OV therapy in cis (left) involves encoding a gene product or therapeutic payload (green) directly in the virus backbone (blue). When a productive infection takes place within cancer cells, the payload is locally expressed at high levels with minimal systemic exposure. This has the advantage of avoiding systemic toxicities and reducing costs because only a single therapeutic (i.e., OV) is required. The disadvantage of this approach is that the expression of the therapeutic payload is linked to the longevity of the virus replication within the tumor. If a therapeutic requires sustained expression over several months, then this approach may be suboptimal. Additionally, if a virus can only be administered by direct intratumoral injection (IT), then the payload will not be optimally expressed in disseminated tumors. Providing a therapeutic in trans with OV administration is required if the complementary treatment is a chemical, small molecule, or form of radiation. It may also be desirable if the therapeutic needs to be dosed for a shorter or longer period than the virus that is found within the tumor. In the setting of trans administration, the costs of using therapeutics together is additive. In order to achieve therapeutically effective doses within the tumor, systemic administration of large amounts of therapeutic with associated toxicities will be required.