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.