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 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.
- [Show abstract] [Hide abstract]
ABSTRACT: Viruses have two opposing faces. On the one hand they can cause harm and disease. A virus may manifest directly as a contagious disease with a clinical pathology of varying significance. A viral infection can also have delayed consequences, and in rare cases may cause cellular transformation and cancer. On the other hand viruses may provide hope: hope for an efficacious treatment of serious disease. Examples of the latter are the use of viruses as a vaccine, as transfer vector for therapeutic genes in a gene-therapy setting, or more directly, as therapeutic anticancer agent in an oncolytic-virus therapy setting. Already there is evidence for antitumor activity of oncolytic viruses. The antitumor efficacy seems linked to their capacity to induce a tumor-directed immune response. Here, we will provide an overview on the development of oncolytic viruses and their clinical evaluation from the Dutch perspective.Human Gene Therapy 08/2014; · 4.02 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Oncolytic viruses (OVs) are viruses with selective ability to replicate & lyse in tumors. Recent results from clinical trials have established their safety yet efficacy remains elusive. We are examining stromal responses elicited upon treatment of intracerebral brain tumor by hrR3 (type 1 Herpes simplex virus (HSV-1) derived OV). Effect of OV treatment on host tumor vasculature. 7 days post intracerebral tumor implantation (D74HveC rat glioma cells), rats were treated with intratumoral injection of hrR3 or PBS. Effect of OV on tumor vasculature was evaluated by i.v injection of FITC- dextran 3 days post OV infection. Our results have uncovered a significant increase in vascular permeability in response to OV treatment of tumors. Quantification of the leaked fluorescent dye in tissue revealed that vascular leakage in OV treated groups was 4 fold higher than in control PBS injected animals (35.7 |[plusmn]| 6 (OV) Vs (8.9 |[plusmn]| 0.3) (PBS). This observation was confirmed on ultra high field, high resolution MRI performed at 8.0-Tesla using ultrasmall particle of iron oxide (USPIO) enhanced gradient echo sequence. Additionally this OV induced vascular leakage was not evident in Cyclophosphamide (CPA) treated immune suppressed rats. These results indicate that increased vessel permeability was a result of endothelial cell activation in response to OV infection. This increased permeability allows for host immune cell infiltration into the tumor which is deleterious to the presence of OV. Effect of OV treatment on angiogenesis. The host immune system uses the OV induced breach in Blood Brain Barrier (BBB) to infiltrate tumor tissue with macrophages resulting in destruction of therapeutic OV. Activated macrophages can secrete VEGF and initiate an angiogenic response. Tumor bearing rats treated with OV or PBS, were sacrificed prior to death and vessel density was evaluated in size matched tumors. The number of vessels/view field, was quantified by RECA-1 and CD31 immunostaining for endothelial cells. Neovascularization was significantly greater in tumors treated with OV compared to control (OV: 101 |[plusmn]| 21.6; versus PBS : 19.8 |[plusmn]| 10) (P = 0.0037). Effect of pretreatment with an anti-angiogenic agent on OV mediated therapy. Based on the above findings we hypothesized that a reduction in tumor blood vessels prior to OV infection would result in reduced tumor infiltration of host inflammatory cells leading to enhancement of OV efficacy. We tested this hypothesis by using Cilengitide (cRGD), a known anti-angiogenic agent & antagonist of integrin |[alpha]|v|[beta]|3. Pretreatment of rats with a single dose of cRGD prior to OV injection significantly increased survival of rats compared to rats treated with a single agent (median survival: PBS: d12; cRGD: d13; OV: d18; cRGD + OV: d22) (P < 0.05 between OV and cRGD + OV).Molecular Therapy 05/2006; · 7.04 Impact Factor
- [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. 01/2014; 4:145.