Appealing as the idea of oncolytic virotherapy may be, its realization is still disconcertingly remote. What this overview emphatically reveals is that the field of retargeting of viruses for therapeutic use is in its early infancy. In fact, for the majority of the viruses studied, scientists are still struggling with the most fundamental aspects of changing their cell tropism. Robust platforms for retargeting have actually not been established yet for any of the viruses. On the positive side, the feasibility of retargeting was, at least in vitro,
demonstrated for an increasing number of viruses in the past years. Clearly the most attractive goal will be to generate oncolytic viruses that carry the retargeting information in their genome. Only then will the viruses be able to sustain their replication in the tumor tissue, irrespective of the retargeting principle used, that is, whether through the modification of the viral attachment protein or through expression of an adapter protein. However, (pre)clinical data on the efficacy—let alone safety—of such transductionally targeted viruses in vivo
are very limited. With one exception (a transductionally and transcriptionally targeted adenovirus [105
]), none of such genetically modified, tropism modified oncolytic viruses have entered phase I clinical trial. This makes it virtually impossible to compare the viruses reviewed here. Thus, many hurdles have yet to be overcome before new oncolytic viruses will reach the clinic. Below, some of the important future tasks and challenges for the field are summarized.
One major challenge at the base of the idea of oncolytic virotherapy is the availability of suitable target receptors on tumor cells. Ideally, such receptors are unique or highly overexpressed in order to provide sufficient specificity for the infection. Recent developments in the proteomics field have already recognized various proteins that are overexpressed in tumor cells as compared to normal tissue and many more will hopefully be identified. It remains, however, questionable whether truly unique tumor surface proteins exist. This stresses the need to increase specificity of oncolytic viruses in other ways. This can be achieved, for example, by combining transductional targeting with either transcriptional targeting or attenuation of the viral genome, both increasing tumor-specific replication. In transcriptional targeting, viral genes essential for replication are placed under control of a tumor-specific promoter—which is particularly feasible for DNA viruses—or under the control of an IRES element in the case of RNA viruses. Attenuation of the viral genome might be achieved by the deletion of viral genes that eliminate functions dispensable in tumor cells, but not in normal tissue. The feasibility of combining both transductional and translational targeting has already been demonstrated for DNA viruses, including adenovirus, while for RNA viruses investigations rather focus on the transductional targeting of attenuated viruses.
The natural tropism of the therapeutic virus is another aspect which needs to be taken into account with regard to safety. Ablation of the native tropism might be required for those viruses naturally infecting humans, to prevent the infection of normal tissue, but also when the virus has a preference for binding, for instance, to blood substances or when it exhibits hepatic tropism, both being a major cause of loss of infectious virus in vivo
. The use of nonhuman viruses for oncolytic therapy gains interest, as such viruses are usually nonpathogenic for humans and, in addition, no preexisting antibodies circulate which might limit their efficacy. However, when adapting to the new host, these viruses might also pose a risk, as was reviewed in [106
In order to achieve effective eradication of all tumor cells, a desirable characteristic of oncolytic viruses is their ability to cause sustained, multiround infection. This can be achieved by viruses genetically redirected through the incorporation of tumor-binding ligands and those having incorporated a bispecific adapter into their viral genome The stability of such recombinant viruses might, however, be a matter of concern, in particular when the targeting protein is required to ablate the natural human tropism. In general, DNA viruses are considered to be more stable than RNA viruses in which, in addition, the mutation rate is relatively high.
Irrespective of the origin of the virus, immunity induced upon (repeated) viral treatment against viral antigens but also against foreign proteins like the bispecific adapters expressed from the viral genome might limit the effectiveness of the therapy. To shield viruses from antibodies, polymers might be used to coat the virion [107
]. Yet, this might compromise the binding of the virus to tumor cells and can technically only be performed upon application and not during lateral spread of the virus. Other ways to increase the delivery of oncolytic virus to tumor cells, especially when applied systemically, might be the use of carrier cells, which have the ability to home to the tumor [108
In conclusion, transductionally targeted viruses may provide a much needed tumor-specific therapy, but researchers will have to face, besides the technological challenges, a delicate balance between safety and effectiveness during development of such new viruses for clinical use. Yet, despite all problems and concerns, the importance of the ultimate goal of winning the fight against cancer warrants the sacrifice of all the energy and creativity needed for its realization.