Immunosuppression promotes reovirus therapy of colorectal liver metastases

Abstract

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 Krasdependent 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.

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

“…However, it may be most effective when utilized in combination with conventional chemotherapy (Harrington et al, 2010). 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.…”

Evaluation of cancer virotherapy with attenuated replicative Semliki forest virus in different rodent tumor models

“…the RNA viruses reovirus and Newcastle disease virus are considered oncotropic by nature. The oncolytic potency of these viruses has already been demonstrated in preclinical studies [2][3][4] and even in clinical (phase I/II) trials. 5 Thus, it appears that a wide variety of different viruses have features that make them good candidates for oncolytic virotherapy.…”

Transient infection of freshly isolated human colorectal tumor cells by reovirus T3D intermediate subviral particles

“…7 Reovirus T3D has shown great preclinical therapeutic efficacy in the treatment of several types of subcutaneous tumors and metastatic lesions formed by tumor cell lines. [8][9][10][11][12] Based on this preclinical evidence, the antitumor activity of reovirus T3D is currently being tested in clinical trials. 13 Many novel therapeutics that show great promise as antitumor compounds in preclinical experiments fail to fulfill this promise in clinical trials.…”