Oncolytic Viral Therapy Using Reovirus

Abstract

Current mainstays in cancer treatment such as chemotherapy, radiation therapy, hormonal manipulation, and even targeted therapies such as Trastuzumab (herceptin) for breast cancer or Iressa (gefitinib) for non-small cell lung cancer among others are limited by lack of efficacy, cellular resistance, and toxicity. Dose escalation and combination therapies designed to overcome resistance and increase efficacy are limited by a narrow therapeutic index. Oncolytic viruses are one such group of new biological therapeutics that appears to have a wide spectrum of anticancer activity with minimal human toxicity. Since the malignant phenotype of tumors is the culmination of multiple mutations that occur in genes eventually leading to aberrant signaling pathways, oncolytic viruses either natural or engineered specifically target tumor cells taking advantage of this abnormal cellular signaling for their replication. Reovirus is one such naturally occurring double-stranded RNA virus that exploits altered signaling pathways (including Ras) in a myriad of cancers. The ability of reovirus to infect and lyse tumors under in vitro, in vivo, and ex vivo conditions has been well documented previously by us and others. The major mechanism of reovirus oncolysis of cancer cells has been shown to occur through apoptosis with autophagy taking place during this process in certain cancers. In addition, the synergistic antitumor effects of reovirus in combination with radiation or chemotherapy have also been demonstrated for reovirus resistant and moderately sensitive tumors. Recent progress in our understanding of viral immunology in the tumor microenvironment has diverted interest in exploring immunologic mechanisms to overcome resistance exhibited by chemotherapeutic drugs in cancer. Thus, currently several investigations are focusing on immune potentiating of reovirus for maximal tumor targeting. This chapter therefore has concentrated on immunologic cell death induction with reovirus as a novel approach to cancer therapy used under in vitro and in vivo conditions, as well as in a clinical setting. Reovirus phase I clinical trials have shown indications of efficacy, and several phase II/III trials are ongoing at present. Reovirus's extensive preclinical efficacy, replication competency, and low toxicity profile in humans have placed it as an attractive anticancer therapeutic for ongoing clinical testing that are highlighted in this chapter.

Concepts for the Production of Viruses and Viral Vectors in Cell Cultures

“…Viral tropism can be engineered by displaying ligands that bind to cell surface receptors unique to cancer cells [10,[30][31][32]. Several genetically modified viruses have been adapted as potent oncolytic agents for clinical trials, including herpesvirus [33], adenovirus [34], poxvirus [35], coxsackievirus [36], polyovirus [37], Newcastle disease virus [38] and reovirus [39]. In October 2015, the US Food and Drug Administration (FDA) granted approval for the first oncolytic virus (talimogene laherparepvec or T-VEC, brand name IMLYGIC) indicated for cutaneous and nodal melanoma.…”

Exploring the antitumor effect of virus in malignant glioma

“…Reovirus is a double-stranded RNA virus that is nonpathogenic in humans and has demonstrated oncolytic activity against GBM (74, 75). Serotype 3 reovirus was found to be oncolytic because its replication depended on activated Ras signaling pathways that are often upregulated in cancer cells, including GBM (74, 76).…”

Untitled

“…Some viruses, such as reoviruses, have natural, inherent tumour selectivity 27,28 . From a general point of view, Oncolytic viruses can be engineered in three ways.…”