Immunosuppression promotes reovirus therapy of colorectal liver metastases

Leiden University, Leyden, South Holland, Netherlands
Cancer Gene Therapy (Impact Factor: 2.42). 09/2006; 13(8):815-8. DOI: 10.1038/sj.cgt.7700949
Source: PubMed


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.

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    • "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. "
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    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.
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    • "It has been demonstrated that suppression of the immune system improved the efficacy of reovirus therapy . Intrahepatic administration of reovirus to liver tumor models has shown that reovirus inhibits tumor growth more efficiently in mice treated with the immunosuppressive drug cyclosporin A [120]. The combination of reovirus and cisplatin significantly delayed tumor growth and prolonged survival compared to reovirus or cisplatin alone treatment in a mouse melanoma model [115]. "

    No preview · Article · Jan 2013 · Journal of Cancer Therapy
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    • "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. "
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    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.
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