Mortality due to colorectal cancer (CRC) is high and is associated with the development of liver metastases. Approximately 40% of human CRCs harbor an activating mutation in the KRAS oncogene. Tumor cells with activated KRAS are particularly sensitive to Reovirus T3D, a non-pathogenic oncolytic virus. The efficacy of virus-based therapies may be positively or negatively modulated by the host immune system. This study was designed to assess the effect of immunosuppression on Reovirus T3D oncolysis of established colorectal micrometastases in the liver. Mouse C26 CRC cells harbor a mutant Kras gene and are susceptible to Kras-dependent oncolysis by Reovirus T3D in vitro. Isolated C26 liver tumors were established in syngenic immunocompetent BALB/c mice by intrahepatic injection. Reovirus T3D therapy was given as a single intratumoral injection in control mice and in cyclosporin A-treated immunosuppressed mice. Tumor growth was analyzed over time by non-invasive bioluminescence imaging. The outgrowth of established CRC liver metastases in immunocompetent mice was efficiently but temporarily inhibited with a single injection of Reovirus T3D. Immunosuppression with cyclosporin A markedly increased and prolonged the therapeutic effect and allowed complete Reovirus T3D-induced tumor eradication in a subpopulation of the mice. We conclude that Reovirus T3D is an effective therapeutic agent against established C26 colorectal liver metastases and that immunosuppression enhances treatment efficacy. Cancer Gene Therapy (2006) 13, 815-818. doi:10.1038/sj.cgt.7700949; published online 10 March 2006.
"Similarly, a high throughput screen of pharmaceutical agents identified a novel drug (Vse1) that could enhance oncolytic virotherapy by disrupting the IFN-induced antiviral response and repressing antiviral gene transcripts (103). Another drug that can be used for immune suppression is cyclosphorine A, which markedly increased and prolonged the therapeutic effect of reovirus therapy of metastatic cancer (104, 105). However, the most common immunosuppressant drug used in the context of oncolytic virotherapy is cyclophosphamide (CPA); a chemotherapeutic alkylating agent that also induces apoptotic cell death. "
[Show abstract][Hide abstract] ABSTRACT: Cancer is a traitorous archenemy that threatens our survival. Its ability to evade detection and adapt to various cancer therapies means that it is a moving target that becomes increasingly difficult to attack. Through technological advancements, we have developed sophisticated weapons to fight off tumor growth and invasion. However, if we are to stand a chance in this war against cancer, advanced tactics will be required to maximize the use of our available resources. Oncolytic viruses (OVs) are multi-functional cancer-fighters that can be engineered to suit many different strategies; in particular, their retooling can facilitate increased capacity for direct tumor killing (oncolytic virotherapy) and elicit adaptive antitumor immune responses (oncolytic immunotherapy). However, administration of these modified OVs alone, rarely induces successful regression of established tumors. This may be attributed to host antiviral immunity that acts to eliminate viral particles, as well as the capacity for tumors to adapt to therapeutic selective pressure. It has been shown that various chemotherapeutic drugs with distinct functional properties can potentiate the antitumor efficacy of OVs. In this review, we summarize the chemotherapeutic combinatorial strategies used to optimize virally induced destruction of tumors. With a particular focus on pharmaceutical immunomodulators, we discuss how specific therapeutic contexts may alter the effects of these synergistic combinations and their implications for future clinical use.
Frontiers in Oncology 06/2014; 4:145. DOI:10.3389/fonc.2014.00145
"Recent studies have used cyclophosphamide, gemcitabine or cisplatin to improve the activity of Reolysin in solid tumors (Smakman et al., 2006; Qiao et al., 2008; Pandha et al., 2009; Sei et al., 2009). The enhanced cytotoxicity observed of the addition of these compounds to reovirus therapy has been largely attributed to suppression of the anti-viral immune response. "
[Show abstract][Hide abstract] ABSTRACT: Oncolytic virotherapy with reovirus has demonstrated anti-cancer activity and minimal toxicity in clinical trials, but the mechanisms underlying these effects have not been fully elucidated. Reolysin, a proprietary formulation of reovirus for cancer therapy, stimulated selective viral replication and apoptosis in multiple myeloma (MM) cells. Reolysin-mediated apoptosis was associated with an induction of endoplasmic reticular (ER) stress-related gene expression, swelling of the endoplasmic reticulum, increases in intracellular calcium levels and a strong induction of the Bcl-2 homology 3 (BH3)-only pro-apoptotic protein NOXA. Knockdown of NOXA expression by short hairpin RNA significantly reduced the pro-apoptotic effects of Reolysin. We next showed that co-administration of Reolysin and bortezomib resulted in the dual accumulation of viral and ubiquitinated proteins, which led to enhanced ER stress, NOXA induction and apoptosis. Importantly, the combination of reovirus infection and proteasomal inhibition significantly decreased tumor burden in a xenograft and syngeneic bone disease model of MM without exhibiting adverse side effects. Our study establishes ER stress stimulation and NOXA induction as novel mediators of reovirus-induced apoptosis. Furthermore, reovirus infection can be used as a promising approach to augment the anti-myeloma activity of bortezomib by promoting additional stress to the endoplasmic reticulum of MM cells.
"Similar effects were observed when CPA was administered with adenovirus, vaccinia virus and reovirus (Qiao et al., 2008b; Thomas et al., 2008; Lun et al., 2009), and a phase I clinical trial with CPA in combination with measles virus has been initiated for patients with multiple myeloma (Myers et al., 2007). Other immunosuppressive drugs, such as cisplatin , cyclosporine and rapamycin, have been utilized with similar success in blocking antiviral inflammatory responses to oncolytic reovirus, adenovirus and vaccinia virus therapy, resulting in enhanced viral replication and improved tumour responses (Smakman et al., 2006; Cheong et al., 2008; Pandha et al., 2009). Due to the fact that immune cells use the tumour vasculature to traffic to tumours, strategies to inhibit vascular permeability associated with an oncolytic virus therapy has been explored. "
[Show abstract][Hide abstract] ABSTRACT: Tumour-specific replicating (oncolytic) viruses are novel anticancer agents, currently under intense investigation in preclinical studies and phase I-III clinical trials. Until recently, most studies have focused on the direct antitumour properties of these viruses. There is now an increasing body of evidence indicating that host immune responses may be critical to the efficacy of oncolytic virotherapy. Although the immune response to oncolytic viruses can rapidly restrict viral replication, thereby limiting the efficacy of therapy, oncolytic virotherapy also has the potential to induce potent antitumoural immune effectors that destroy those cancer cells, which are not directly lysed by virus. In this review, we discuss the role of the immune system in terms of antiviral and antitumoural responses, as well as strategies to evade or promote these responses in favour of improved therapeutic potentials.
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