Advances in oncolytic virus therapy for glioma

Abstract

The World Health Organization grossly classifies the various types of astrocytomas using a grade system with grade IV gliomas having the worst prognosis. Oncolytic virus therapy is a novel treatment option for GBM patients. Several patents describe various oncolytic viruses used in preclinical and clinical trials to evaluate safety and efficacy. These viruses are natural or genetically engineered from different viruses such as HSV-1, Adenovirus, Reovirus, and New Castle Disease Virus. While several anecdotal studies have indicated therapeutic advantage, recent clinical trials have revealed the safety of their usage, but demonstration of significant efficacy remains to be established. Oncolytic viruses are being redesigned with an interest in combating the tumor microenvironment in addition to defeating the cancerous cells. Several patents describe the inclusion of tumor microenvironment modulating genes within the viral backbone and in particular those which attack the tumor angiotome. The very innovative approaches being used to improve therapeutic efficacy include: design of viruses which can express cytokines to activate a systemic antitumor immune response, inclusion of angiostatic genes to combat tumor vasculature, and also enzymes capable of digesting tumor extra cellular matrix (ECM) to enhance viral spread through solid tumors. As increasingly more novel viruses are being tested and patented, the future battle against glioma looks promising.

Fig. 1

The p16 pathway blocks the CDK4-CDK6-cyclin-D complex which increases the phosphorylation state of RB, causing it to release the transcription factor E2F. Free E2F mediates the transcription of several cellular genes that are involved in G1/S progression, including ribonucleotide reductase (RR). In normal non cycling cells there is no cellular RR hence Herpes simplex virus (HSV-1) strains with mutations in viral ICP6 gene (encoding for viral counterpart of cellular RR), can not promote DNA synthesis and viral replication. Loss of p16 or RB function frequently found in neoplastic cells dys-regulates E2F activity, and leads to increased production of cellular proteins such as RR. This is exploited by HSV-1 defective in ICP6 to replicate in cancer cells.

Fig. 2

Viral infection of cells initiates the homo-dimerization and subsequent phosphorylation and activation of interferon-induced, double-stranded RNA-activated protein kinase (PKR). Activated PKR phosphorylates its natural substrate, the alpha subunit of eukaryotic protein synthesis initiation factor-2 (EIF2-alpha), leading to the inhibition of cellular protein synthesis. HSV-1 encodes for γ34.5, a viral protein that mediated protein phosphatase 1α to dephosphorylate EIF2-alpha, releasing the translational block initiated in normal cells upon infection. In the absence of viral γ34.5 gene the viral replication is blocked by cellular responses in normal cells. Cancer cells with an activated RAS/MEK pathway suppress PKR autophosphorylation, hence allowing γ34.5^−/− virus to replicate in them.

Fig. 3

A: Wild type Adenovirus encodes for viral E1A protein that can bind to and inactivate cellular pRb protein. Inactivation of Rb releases E2F transcriptional factor driving the host cell into a proliferative phase, facilitating viral replication. B; Adenoviruses with a mutant E1A, can not inactivate cellular Rb, and can hence replicate only in cells with a mutant p16/pRb pathway.