Introduction of Vesicular Stomatitis Virus as Oncolytic Virus
Recently, significant progress has been made in the development of immune-based cancer therapeutics in which the organism's immune system is harnessed to combat invading cancer. Oncolytic viruses (OVs) offer a unique treatment option, because of their impressive multimodal mechanism of action. They are probably well-known for their inherent ability to induce tumor debulking through direct tumor cell lysis, but they additionally provide the potential to break immune tolerance and stimulate strong immune responses targeting uninfected tumor cells and distant metastases. Thus, they have been implemented in rationally designed combination therapies involving OVs as immunotherapeutic. Here, vesicular stomatitis virus (VSV) represents an extremely attractive vector system for viral-based immunotherapies owing to its natural tumor specificity, rapid replication, cell-killing kinetics, as well as its natural capacity to stimulate immune responses.
VSV Biology
VSV is a negative-strand RNA virus originated from the Rhabdoviridae family with a relatively compact genome containing ~11,000 nucleotides encoding for 5 distinct viral proteins. The VSV glycoprotein (G protein) can mediate viral attachment and fusion to host cells by extensively expressed low-density lipoprotein (LDL) receptor, followed by receptor-mediated endocytosis and internalization into endosomes. Subsequently, the low endosomal pH initiates a conformational change in the G protein, stimulating fusion to the endosomal membrane and resulting in the secretion of the viral genome into the cytosol and the beginning of the replication process. Although VSV can infect a broad range of host cells, the replication is restricted to cells that are defective in their antiviral interferon pathways, offering an inherent mechanism for tumor specificity.
Fig.1 The VSV replication cycle. (Lichty, 2004)
The Development of Oncolytic VSV Therapy
OV therapy as an emerging anti-cancer approach has obtained much attention in current years that exploit viruses to selectively infect and lyse cancer cells, while not harming healthy cells. VSV is under intense development as an OV since a variety of favorable characteristics. In terms of this powerful system, multiple strategies have been applied to further promote the immune-stimulating potential of VSV and synergize these responses with the direct oncolytic effect. Effective strategies include the following:
- modification of endogenous virus genes to activate interferon's induction;
- virus-mediated expression of cytokines or immune-stimulatory candidates to increase anti-tumor immune responses;
- vaccination methods to stimulate adaptive immune activities against a tumor antigen;
- combination with adoptive immune cell therapy for latently synergistic therapeutic responses.
Fig.2 Scheme of VSV-based OV therapy. (Hastie, 2012)
VSV is considered as a promising OV material, triggering with the inherent qualities of wild-type VSV. As with any OV, VSV has its limitations required to be overcome for future clinical success. Compared with other types of OVs, VSV is beneficial by virtue of a combination of some factors, such as its well-studied biological features, the relative independence of a receptor or cell cycle, ability to infect many different laboratory cell lines and to generate high virus yields, cytoplasmic replication without risk of host-cell transformation, lack of pre-existing immunity, and a small, easily manipulated genome in humans. In the last ten years, a multitude of recombinant VSVs has been produced by reverse genetics, aiming at generating more robust OVs that function synergistically with host immunity and other therapies to reduce or eliminate tumor burden.
Furthermore, analyzing the mechanisms of VSV onco-selectivity is essential for creating novel and safer OVs for selective replication in tumor cells. Several cellular proteins (e.g. AKT, eIF2β, eIF4E, PKR, and NFAR1/2) have been demonstrated to play a key role in mRNA translation as a determinant of VSV onco-selectivity.
References
- Lichty, B.D.; et al. Vesicular stomatitis virus: re-inventing the bullet. Trends Mol Med. 2004, 10(5): 210-216.
- Hastie, E.; et al. Vesicular stomatitis virus as a flexible platform for oncolytic virotherapy against cancer. J Gen Virol. 2012, 93(Pt 12): 2529-2545.