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Preparing an oncolytic poliovirus recombinant for clinical application against glioblastoma multiforme

https://doi.org/10.1016/j.cytogfr.2010.02.005Get rights and content

Abstract

PVS-RIPO is a genetically recombinant, non-pathogenic poliovirus chimera with a tumor-specific conditional replication phenotype. Consisting of the genome of the live attenuated poliovirus type 1 (Sabin) vaccine with its cognate IRES element replaced with that of human rhinovirus type 2, PVS-RIPO displays an inability to translate its genome in untransformed neuronal cells, but effectively does so in cells originating from primary tumors in the central nervous system or other cancers. Hence, PVS-RIPO unleashes potent cytotoxic effects on infected cancer cells and produces sustained anti-tumoral responses in animal tumor models. PVS-RIPO presents a novel approach to the treatment of patients with glioblastoma multiforme, based on conditions favoring an unconventional viral translation initiation mechanism in cancerous cells. In this review we summarize advances in the understanding of major molecular determinants of PVS-RIPO oncolytic efficacy and safety and discuss their implications for upcoming clinical investigations.

Introduction

The idea of enlisting the help of human pathogens in the fight against cancer first emerged from early anecdotal reports of spontaneous tumor remissions following immunization with live attenuated viruses or co-incidental infection (reviewed in [1]). More than 100 years later, a multitude of viral agents have been proposed to serve such purposes and are at various stages of pre-clinical or clinical testing. The unifying principle underlying each of these is conditional replication and cytotoxicity in cancerous cells combined with reduced propagation in normal tissues and, hence, pathogenic potential [2]. Strategies to devise oncolytic viral agents can be roughly divided in two groups according to diverse mechanisms of tumor selectivity. Certain viruses exhibit inherent selective cytopathogenicity for transformed human cells, because viral replication/pathogenesis is naturally restricted in normal human tissues. Examples for this group include human orphans, e.g. reovirus [3], or animal viruses with lacking human tropism, e.g. vesicular stomatitis virus [4] or myxoma virus [5]. A proposed common mechanistic basis for tumor selectivity of these agents is that virus propagation in normal human tissues is tightly controlled via innate immune responses, accounting for their low inherent pathogenic potential. In contrast, tumor cells, which commonly exhibit deficient innate immunity [6], may permit replication and cell killing of human orphan viruses, e.g. reovirus. Viruses with lacking human host range may exhibit similar specificity because viral mechanisms to counter innate host defenses in their respective host species are ineffective in normal human cells [7]. However, these viruses may exhibit significant cytotoxicity in tumor cells with defective innate defenses, due to removal of the primary barrier to viral replication in cells of a foreign host.

Other viruses under consideration for use as oncolytic agents require sophisticated genetic manipulations in order to achieve tumor selectivity because of inherent pathogenic potential. Examples include adenovirus [8], herpes simplex virus (HSV) [9], or poliovirus [10]. A plethora of genetic manipulations have been introduced to viral genomes to achieve conditional replication phenotypes. For oncolytic HSVs these include deletion of genes deemed essential for replication in normal cells but dispensable in cancerous cells (e.g. the HSV γ34.5 and ribonucleotide reductase genes [11]), insertion of tumor-specific promoters [12], or manipulation of genetic elements involved in translation control [13].

Section snippets

Limitations of genetic manipulation of oncolytic viruses

Intuitively, basing oncolytic virus strategies on pathogenic viruses has certain advantages. For example, the documented inherent capacity of neuroinvasive HSVs or poliovirus to disseminate in the human brain may aid in targeting regionally diffuse glioma. Also, the availability of specific chemotherapy (e.g. against HSV) or vaccines (e.g. against poliovirus) can help to mitigate concerns about the potential unintended public health consequences of virus administration to cancer patients.

The rationale for oncolytic polioviruses

The principal reason to consider poliovirus for cancer targeting is simple: the poliovirus receptor, nectin-like molecule 5 (Necl-5), is broadly up-regulated in malignancy. Receptor tropism is an Achilles heel for many oncolytic virus strategies, because tropism for intended tumor targets may be inherently poor or difficult to determine empirically (e.g. due to multiple molecular entities with complex control over host cell binding/entry or in cases where receptor identity is unknown).

A poliovirus recombinant with tumor-specific replication/cytotoxicity

Inherent neuropathogenicity of wild-type poliovirus prevents its consideration for therapeutic purposes. Conditional replication of poliovirus in cancerous cells was achieved by manipulating the viral 5′UTR and a cis-acting genetic element involved in translation regulation, the internal ribosomal entry site (IRES) in particular. The prototype oncolytic poliovirus, termed PVS-RIPO, is the live attenuated poliovirus type 1 (Sabin) containing a heterologous IRES derived of human rhinovirus type 2

Genetic stability of PVS-RIPO

Plans for clinical tests of PVS-RIPO demanded rigorous investigation of the major biosafety concern, genetic instability (see above). We observed the remarkable genetic stability of PVS-RIPO upon long-term serial passage in HeLa cells in the laboratory, in preliminary pre-clinical studies in experimental animals [10] and during good-manufacturing-practice production of the agent in VERO cells (unpublished data). However, to systematically address concerns that PVS-RIPO, while proliferating in

PVS-RIPO and translation control in cancer

Despite its reduced requirements for protein synthesis initiation, even picornavirus IRES-mediated translation depends on initiation factors mediating ribosome recruitment to RNAs. Therefore, an obvious level of regulation of PVS-RIPO translation and growth, or picornavirus propagation in general, is controlled activity of translation factors. This concept is supported by the fact that both central initiation factors critically involved in ribosome recruitment at eukaryotic mRNAs, eIF4E and

Summary and outlook

Ten years of pre-clinical investigation of PVS-RIPO, the molecular mechanisms responsible for neuro-attenuation and GBM-specific cytotoxicity, have revealed a surprisingly complex interplay of extracellular factors, e.g. receptor expression and/or tissue type-specific receptor function, and intracellular factors, e.g. the protein synthesis machinery and its regulation in malignancy. These studies suggest that conditional replication phenotypes associated with oncolytic viruses can rarely be

Christian Goetz is a PhD candidate in the Dept. of Molecular Cancer Biology at Duke University. He received his undergraduate degree at the Eberhard Karls Universitaet in Tuebingen, Germany and at the University of Michigan. He joined Dr. Gromeier's group in 2007 and his studies have focused on the tumor cell killing mechanism of oncolytic polioviruses. He has been particularly interested in oncogenic signaling pathways controlling translation of the viral genome.

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    Christian Goetz is a PhD candidate in the Dept. of Molecular Cancer Biology at Duke University. He received his undergraduate degree at the Eberhard Karls Universitaet in Tuebingen, Germany and at the University of Michigan. He joined Dr. Gromeier's group in 2007 and his studies have focused on the tumor cell killing mechanism of oncolytic polioviruses. He has been particularly interested in oncogenic signaling pathways controlling translation of the viral genome.

    Matthias Gromeier, MD, is associate professor in the Dept. of Surgery, Div. of Neurosurgery at Duke Univ. Medical School. He is a former recipient of a Burroughs Wellcome Career Award in the biomedical sciences. His research interests are in regulation of protein synthesis in cancer and novel ways to target abnormal translation regulation, e.g. via the use of oncolytic viruses.

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