Oncolytic Viruses for Cancer Therapy I. Cell-External Factors: Virus Entry and Receptor Interaction

Abstract

After being recognized for their anti-neoplastic properties at the beginning of the last century, viruses are again being considered for use as therapeutic agents against cancer. Certain virus species have a propensity to replicate within transformed cells, which are commonly rendered vulnerable due to tumor-specific defects in their defense against viral infection. Other viruses have been modified to subject them to tumor-specific growth conditions. Oncolytic viruses carry the promise to efficiently target cancer cells for destruction and spread throughout tumor tissue to reach distant neoplastic loci without causing collateral damage to healthy tissues. In contrast to conventional cancer chemotherapy, viral anti-neoplastic agents require complex interactions with the host organism to reach their target and to unfold their oncolytic activity. Recent progress in the elucidation of the molecular mechanisms of viral pathogenesis has opened up new opportunities to manipulate virus-host interactions, generating effective anti-tumor strategies. On the other hand, significant obstacles towards the application of safe and efficacious viral therapies have become apparent. These frequently relate to the lack of cell culture and animal tumor models that accurately reflect the characteristics of cancerous tissues in patients. Throughout the past century, viral therapeutics against cancer have evolved into a new class of treatment strategies characterized by unique opportunities and challenges. A growing number of oncolytic viruses has entered clinical investigation or is scheduled to do so in the near future. Great efforts are being undertaken to rekindle an old idea and, with the help of new technologies, to realize its promise of new treatment facilities for cancer.

History of Oncolytic Viruses: Genesis to Genetic Engineering

“…Measles virus, for example, was first attenuated by serial passage in cultured cells, then genetically engineered to enhance its oncolytic potency and tumor specificity. [98][99][100][101][102] By and large, through a variety of mechanisms that have recently been reviewed [103][104][105][106][107][108][109][110] these clinically tested oncolytic viruses have shown strong specificity for neoplastic tissue.…”

Intravenous injection of oncolytic picornavirus SVV-001 prolongs animal survival in a panel of primary tumor–based orthotopic xenograft mouse models of pediatric glioma

“…Previous virological studies indicate that binding to target cell receptors is a critical initiating step in the virus life cycle. 34 Sialic acids are shown to be used by a number of viruses as a component of their cellular receptors and may lead to restrictions in host range, tissue tropism, and pathogenesis/oncolytic activities. 37 An example of this can be seen by the preference of avian influenza for a2,3-linked sialic acid and growth of this virus in intestinal cells in birds, whilst human influenza uses a2,6-linked sialic acid and grows in cells of the respiratory tract.…”

“…Previous virological studies indicate that binding to a target cell receptor is a critical initiating step in the virus life cycle. 34,35 A number of DNA and RNA viruses, including members of the Picornaviridae family, 36,37 have been shown to use sialic acids, which are often found at the terminus of the oligosaccharide attached to glycoproteins, glycolipids, or proteoglycans, as a component of their cellular receptor. Whether the infection of SVV-001 is mediated by sialic acids remains elusive to determine.…”

The Use of a Tropism-Modified Measles Virus in Folate Receptor–Targeted Virotherapy of Ovarian Cancer

“…These protective mechanisms are in general defective in tumor cells, making them permissive to viral infections (38). Recent progresses in molecular engineering and virus rescue systems have enabled us to control tumor selectivity in new generations of ''designer'' tumor-selective viruses; these strategies either target defects in the intracellular genetic pathways or receptor usage (39,40). Here, we have ablated the native tropisms of measles virus and redirected virus attachment, entry, and cytopathic effects to the tumor antigen via a scFv.…”