Oncolytic virus therapy for glioblastoma multiforme: concepts and candidates

Abstract

Twenty years of oncolytic virus development have created a field that is driven by the potential promise of lasting impact on our cancer treatment repertoire. With the field constantly expanding-more than 20 viruses have been recognized as potential oncolytic viruses-new virus candidates continue to emerge even as established viruses reach clinical trials. They all share the defining commonalities of selective replication in tumors, subsequent tumor cell lysis, and dispersion within the tumor. Members from diverse virus classes with distinctly different biologies and host species have been identified. Of these viruses, 15 have been tested on human glioblastoma multiforme. So far, 20 clinical trials have been conducted or initiated using attenuated strains of 7 different oncolytic viruses against glioblastoma multiforme. In this review, we present an overview of viruses that have been developed or considered for glioblastoma multiforme treatment. We outline the principles of tumor targeting and selective viral replication, which include mechanisms of tumor-selective binding, and molecular elements usurping cellular biosynthetic machinery in transformed cells. Results from clinical trials have clearly established the proof of concept and have confirmed the general safety of oncolytic virus application in the brain. The moderate clinical efficacy has not yet matched the promising preclinical lab results; next-generation oncolytic viruses that are either "armed" with therapeutic genes or embedded in a multimodality treatment regimen should enhance the clinical results.

Figure 1. Timeline of oncolytic virus development from glioblastoma therapy

This schematic diagram lists viruses with oncolytic potential based on their first description in preclinical glioma studies starting in 1991. Subsequent major developments within one virus group are included. Viruses are color-coded based on their pathogenic background as human pathogen (orange), human vaccine (yellow), or non-human pathogen (blue).

Figure 2. Mechanisms for selective oncotropism and oncolysis

Molecular mechanisms determining tumor-selective viral infection and replication are grouped schematically based on the cellular compartment of tumor-virus interaction. (I) Extracellular compartment. Some oncolytic viruses (OVs) can exert selective tumor suppression through induction of cytokine production. OV’s can selectively attack vasculature in tumors and tumor-associated matrix proteases can augment virus attack. (II) Tumor cell membrane. Naturally occurring oncotropic viruses bind to tumor-associated surface receptors. OVs can be engineered to enhance tropism to aberrant tumor receptors. (III) Cytosol. Tumors with aberrant signaling cascades (RAS) and antiviral defense (PKR and IFN) can be targeted by a number of OVs. (IV) Nucleus. Activated cell cycle and nucleotide synthesis in transformed cells enable replication of gene-deleted OV mutants. Expression of viral genes can be engineered to be under control of tumor-specific promoters. Abbreviations: IL, interleukin; GM-CSF, Granulocyte-macrophage colony-stimulating factor; LCMV, lymphocytic choriomeningitis virus; PKR, protein kinase R; TK, thymidine kinase, GFAP, glial fibrillary acidic protein.