Immunosuppression promotes reovirus therapy of colorectal liver metastases

Department of Surgery, University Medical Center Utrecht, GA Utrecht, The 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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    • "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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    • "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. "
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