Oncolytic Virotherapy: Combining First-Rate Science with an Unmet Clinical Need

O ncolytic virotherapy is intended to exploit cancer-selective replication of lytic viruses to kill tumor cells, allowing viral amplification in situ that facilitates infection of adjacent cells and spread through tumor masses. In this way virotherapy promises to combine high selectivity (defined by the factors influencing viral replication) with great potency. Approaches such as virotherapy differ from more conventional cancer treatments by producing the highest concentration of the therapeutic agent (in this case the virus) within tumor cells and nodules, not in the bloodstream. In this way the approach should achieve a high therapeutic index.

Some oncolytic viruses are natural forms, for example, vaccine strains of animal viruses, for which cancer selectivity is defined by deficiencies in tumor-associated defenses, particularly interferons. Other oncolytic viruses have been designed for cancer selectivity at the transcriptional level (using target-associated promoters to regulate key viral genes) or the protein level (where genetic deletions in the virus are complemented selectively by the tumor phenotype), and others have been selected from diverse virus libraries by natural selection. All of these approaches offer the same overall benefit—cancer-selective replication and lysis and potent amplification in situ.

Progress in the field is currently fast. The first product license was granted for adenovirus H101 (Shanghai Sunway Biotech) by China's State Food and Drug Administration (SFDA) for the treatment of head and neck cancer in 2005, and at present there are advanced phase trials ongoing around the world using oncolytic reovirus, vaccinia, and herpesvirus. The field has stimulated several large and focused meetings, the most recent of which was the 6th International Conference on Oncolytic Viruses as Cancer Therapeutics, held in Las Vegas, Nevada in March 2011 (www.oncolyticvirus.info/Home/Welcome.html), which attracted some 200 delegates. The value of designing lytic viruses to kill cancer cells selectively is now clear, and engineering them simultaneously to express therapeutic transgenes provides another level of intervention that is limited only by our understanding of cancer biology.

Adenovirus has always been at the fore of virotherapy, partly because it is well characterized and amenable to genetic manipulation, but also because it can be produced relatively easily under Good Manufacturing Practice (GMP) conditions in therapeutic doses. Although intravenous administration of the common serotype 5 adenovirus has not led to success in humans, presumably because of significant preexisting immunity that can neutralize the virus before it reaches a tumor, more imaginative routes of delivery or the use of different adenoviral serotypes affords a viable way forward.

This issue of Human Gene Therapy contains two important studies developing oncolytic adenoviruses to treat melanoma. Quirin and colleagues (2011) have built on previous studies using “armed” oncolytic adenoviruses, gaining specificity of viral replication for melanoma/melanocytes by using the tyrosinase promoter to drive E1A expression. They also engineered expression of the therapeutic cargo to be restricted to cells supporting replication of viral DNA by inserting the therapeutic proteins either directly or indirectly under the control of the major late promoter. Of crucial importance, they showed a distinction between controlling expression by inserting a splice acceptor site (which gave greater fidelity of expression related to viral E1A expression) and an internal ribosome entry site (IRES). The IRES strategy gave greater levels of expression than the splice acceptor, although it was less tightly controlled between “permissive” cells and “nonpermissive” cells. They conclude that IRES strategies can be more useful when higher abundance of expression is required, although splice acceptors give more tightly defined viral performance.

By expressing pharmacologically active transgenes from the virus, virotherapy has the potential for “gain of function” kill mechanisms, rather than relying solely on cellular death pathways to respond to cellular insults (normally the case with low molecular weight chemotherapeutics). One promising mediator is TRAIL (tumor-necrosis-related apoptosis-inducing ligand); also in this issue, Fecker and colleagues have investigated the utility of expressing TRAIL from a melanoma-selective oncolytic adenovirus. Again regulating E1A expression using the tyrosinase promoter, TRAIL is expressed from a doxycycline-dependent promoter and is intended to mediate killing more efficiently than other approaches in cells that show only a restricted tendency to apoptose. In the studies shown, although viral replication and doxycycline-induced killing are efficient in many melanoma cell lines and animal models, some lines showed signs of TRAIL resistance and were resistant to the approach. Although initially frustrating, this study shows the potential of the approach and immediately draws attention to the value of designing multicomponent killing strategies designed to avoid any aspect of cross-resistance.

The use of adenovirus for virotherapy allows well-defined assessment of new molecular therapeutic strategies, aiming to define potent approaches for clinical development. The potential for “gain of function” effects on tumor cells is unique in the field of cancer therapy and provides this discipline with a range of therapeutic approaches never previously addressed.