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.

Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer

“…A growing body of preclinical and clinical data suggests that oncolytic viral therapy could be an effective therapeutic modality in the treatment of advanced cancer. [5][6][7][8][9][10][11] Various strains of viruses, such as adenovirus, 12 herpes simplex virus, 13 Newcastle disease virus, measles virus, vesicular stomatitis virus and vaccinia virus 14 are being analyzed for their oncolytic capacity; some of these viruses have progressed to the clinical trial phase. Herpes simplex virus type 1 (HSV 1) is an ideal candidate for oncolytic viral therapy because of the following reasons: (a) it infects a broad range of hosts; (b) it causes lyses of the host cell at the end of viral replication; (c) it has a very large genome and therefore harbors many non-essential genes, mostly related to neuroinvasiveness that are expendable and can be replaced during the recombinant engineering process; (d) it can be controlled by antiviral drugs in the event of uncontrolled replication; and (e) its genome remains as an episome and does not incorporate in to the host genome, avoiding the risk of introducing mutations.…”

Advance in herpes simplex viruses for cancer therapy

“…As a consequence of genetic modification, ICP6/34.5-deleted HSV imposes low pathogenicity to normal tissue and high oncolytic capacity to tumor cells. Multi-genes deletions confer great selectivity and safety on HSV; however, deletions of mutations lead to a reduction in neurovirulence and clearness of the virus by host immune response [14,15]. HSV oncolytic nature is determined by lystic genes.…”

HSV Recombinant Vectors for Gene Therapy

“…Innate immunity is critically important in limiting wt viral infections and in the context of HSV oncolytic therapy, this branch of the immune system appears to be a potent obstacle for achieving oncolytic vector replication and tumour destruction [330]. In this regard, drugs that inhibit innate immune response have been shown to enhance glioma virotherapy [235].…”

“…As a further improvement in oncolytic virotherapy, it has been observed that apoptotic bodies produced upon viral infection and their subsequent engulfment by APCs can potentiate cytotoxic T lymphocyte activity and the anti-tumour response. The potential to exploit this in conjunction with OV therapy to enhance anti-tumour immunity is only beginning to be realized and needs to be further investigated [330]. …”