Intelligent design: combination therapy with oncolytic viruses

Abstract

Metastatic cancer remains an incurable disease in the majority of cases and thus novel treatment strategies such as oncolytic virotherapy are rapidly advancing toward clinical use. In order to be successful, it is likely that some type of combination therapy will be necessary to have a meaningful impact on this disease. Although it may be tempting to simply combine an oncolytic virus with the existing standard radiation or chemotherapeutics, the long-term goal of such treatments must be to have a rational, potentially synergistic combination strategy that can be safely and easily used in the clinical setting. The combination of oncolytic virotherapy with existing radiotherapy and chemotherapy modalities is reviewed along with novel biologic therapies including immunotherapies, in order to help investigators make intelligent decisions during the clinical development of these products.

Figure 1

Model of the mechanism of synergy between γ34.5-deleted herpes viruses and conventional cancer therapies. γ34.5-deleted herpes viruses are favored for oncolytic virotherapy because they show reduced neurotoxicity. Deletion of the γ34.5 gene also results in attenuation of viral replication in tumor cells. Interestingly, γ34.5 shows significant structural homology to a portion of human GADD34, a protein involved in the cells response to DNA damage. γ34.5 is responsible for dephosphorylation of the eukaryotic translation initiation factor eIF-2a, which is required for translation of both host and viral proteins. Radiation or chemotherapy-induced upregulation of GADD34 functionally replaces the γ34.5 protein in infected tumor cells leading to increased viral protein synthesis and production of infectious virus particles.

Figure 2

Model of tumor killing following treatment with combination oncolytic virotherapy and targeted radionuclide therapy. Initial sites of virus infection often occur in distinct foci surrounding blood vessels (if delivered intravenously) or along the needle track (if delivered intratumorally). Preclinical data indicates that spreading of the virus from these initial sites may be limited. Incomplete transduction of large tumors remains a barrier to effective oncolytic virotherapy. (a) Combination oncolytic virotherapy and targeted radionuclide therapy overcomes the barrier of incomplete transduction due to the radiation cross-fire effect. Uninfected cells falling within the area of the path length (depicted by the dashed lines) will be exposed to radiation resulting in DNA damage and subsequent cell death. (b) Enlarged view of the mechanism of killing at each foci of infection. Infected cells express the virally encoded receptor (for example, vvDD-SSTR2) at the cell surface. The receptors are specifically bound by their cognate radiolabeled peptide analogue from which radiation is emitted. Radiation is emitted in all three-dimensions from the site of origin with a maximum tissue penetration distance defined by the path length (x). Virally induced oncolysis and radiation-induced apoptosis will result in significantly increased tumor cell death relative to either therapy alone.