The global burden of cancer continues to increase, and with it the urgent need to develop new treatments for common and rare malignancies. Oncolytic viruses (OV) have immense potential as cancer immunotherapeutics. Advances in molecular biology, immunology, genetic engineering, virology and our increased understanding of the complexity of the tumour microenvironment (TME) have supported their development over the last 30 years.

Originally regarded as novel cytotoxics (viral oncolysis), it was clear early on that tumour killing by OV led to innate and adaptive immune responses, migration of inflammatory cells into the TME as well as antigen-specific responses and induction of immune memory. Progress with wild type, bioselected and engineered OV continues and as yet, frustratingly, it is unclear which is the ‘best’ or most efficacious virus and/or payload, delivery method, dose, treatment schedule or type of cancer to treat. Both preclinically and in patient trials I have investigated a number of OV and number of payloads and combinations including chemotherapy, radiotherapy, immune checkpoint inhibitors, tyrosine kinase inhibitors and epigenetic modifiers. Enormous progress with oncolytic herpesvirus type1, vaccinia virus, adenovirus, reovirus and measles virus in the clinic have allowed evaluation in the context of phase 2 and phase 3 studies. The most successful strategy to date has been Talimogene laherparepvec (T-VEC), an oncolytic herpesvirus type 1 expressing GM-CSF which I evaluated as principal investigator in the pivotal phase 1 study, and which was granted FDA approval in 2010. This virus is now used routinely in the national health service as a treatment for malignant melanoma. Other viruses such as CG0070 (adenovirus expressing GM-CSF) have recently received FDA approval for the treatment of non-muscle bladder cancer and will also enter the clinical arena.

Despite a modest number of studies being approved or even reaching the phase 2/3 stage, the continuing interest in these agents is based on their ability to perform as multifunctional immunotherapeutics through numerous complex mechanisms. OV can quickly alter the TME by inflammation, induce anti-tumour immunity by triggering of immunogenic cell death in cancer cells, trigger innate and adaptive immune responses and making otherwise immune checkpoint inhibitor refractory cancer more conducive to responding by combination with virus killing. Their clinical safety profile has been very favourable with no reversion to wild type or toxicity due to latency.

The large number of failed trials, however, reflect our limitations despite having at our disposal these agents with disease modifying potential. These limitations include our inability to identify optimal payload (single, multiple) and choice of target. As most OV programs have not targeted specific cancers from the onset, almost all are limited by impaired infection, impaired replication3

and poor immune activation in certain cancers through their TME make-up (hypoxia, acid environment, pro-tumour cell infiltrate, collagen and desmoplastic reactions making the tumour less vascular and increasing intra-tumoral interstitial pressure). In addition, suboptimal delivery through neutralisation by anti-viral antibodies, binding to liver/spleen and injection route reduces the intra-tumoral biodistribution and therefore magnitude of viral killing and downstream effectors.

Many of these issues are being addressed now. It may be that we already have one or more ‘game changing’ viruses already if we could use them optimally. Attention is now sharply focused to overcome these known limitations. These include careful patient selection (e.g. limiting only to those expressing very high levels of target and by other biomarkers), treating in the neoadjuvant or adjuvant context where there is a less hostile TME and lower disease burden, use of adaptive trial design and novel delivery of OV through attenuation of antiviral responses and/or the use of nanoparticle carriers. This next stage will begin to see OV moving to the first and second line setting for common and rare cancers.

Finally, one solution may be designing an oncolytic virus specifically based on the unique biology of a specific cancer rather than conventionally developing a more generic OV and apply to multiple cancers, and then spending enormous resources to see which indication it works best in. Our oncolytic herpesvirus expressing a TLR5 agonist and IL-15 has been engineered specifically for the treatment of non-muscle invasive bladder cancer, based on the complex biology of this disease at the non-invasive stage, and its response to BCG. This approach may herald an alternative, rapid, focused and resource-efficient perspective for the treatment of other cancers, and extend to malignancies that remain unresponsive to current cancer treatments.