Supplementary Figure from Immune Activity and Response Differences of Oncolytic Viral Therapy in Recurrent Glioblastoma: Gene Expression Analyses of a Phase IB Study
Katherine E. MillerKevin A. CassadyJustin C. RothJennifer N. ClementsKathleen M. SchiefferKristen LeraasAnthony R. MillerNripesh PrasadJianmei W. LeavenworthInmaculada AbanRichard J. WhitleyG. Yancey GillespieElaine R. MardisJames M. Markert
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Supplementary Figure from Immune Activity and Response Differences of Oncolytic Viral Therapy in Recurrent Glioblastoma: Gene Expression Analyses of a Phase IB StudyIn the present paper, we address by means of mathematical modeling the following main question: How can oncolytic virus infection of some normal cells in the vicinity of tumor cells enhance oncolytic virotherapy? We formulate a mathematical model describing the interactions between the oncolytic virus, the tumor cells, the normal cells, and the antitumoral and antiviral immune responses. The model consists of a system of delay differential equations with one (discrete) delay. We derive the model’s basic reproductive number within tumor and normal cell populations and use their ratio as a metric for virus tumor-specificity. Numerical simulations are performed for different values of the basic reproduction numbers and their ratios to investigate potential trade-offs between tumor reduction and normal cells losses. A fundamental feature unravelled by the model simulations is its great sensitivity to parameters that account for most variation in the early or late stages of oncolytic virotherapy. From a clinical point of view, our findings indicate that designing an oncolytic virus that is not 100% tumor-specific can increase virus particles, which in turn, can further infect tumor cells. Moreover, our findings indicate that when infected tissues can be regenerated, oncolytic viral infection of normal cells could improve cancer treatment.
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Oncolytic virus therapy is an area in experimental cancer therapy that is under active investigation. A wide variety of viruses have shown huge potent oncolytic activity against human tumors in cell and animal models without major side effects. Several strains have already being tested in clinical trials in patients. Virotherapy is making promising progress for the treatment of malignancies. Nonetheless, when used in patients, the response rate to oncolytic virus is low. One of the main ways to increase oncolytic capacity is to refuse of excessive attenuation and to use the wild type of oncolytic strains. Naturally occurring oncolytic viruses (OVs) have shown their high cancer-targeted antitumor effects with selectively replication and destroying tumor cells while sparing normal cells, because of defects in IFN-signaling pathways in tumor cell lines. Newcastle disease virus (NDV) is one of the promising therapeutic agent for virotherapy. It belongs to avian paramyxovirus (APMV-1) that is able to infect over 240 species of birds and induce severe disease. However, NDV is not a human pathogen. Newcastle disease virus exhibits effectively oncolytic activity in a range of tumors in pre-clinical and clinical studies. We have previously reported in vitro oncolytic effects of three wild NDV strains. Here we demonstrate data that describe oncolytic capacity NDV collection gathered in 2008–2014, Russia. Antitumor effect of NDV strains on a panel of tumor human cell lines (HCT116, MCF7, A549, HeLa, Skbr, H1299) were investigated. Cell viability was examined over 96 hours by MTT assay. Dose-dependent cell cytotoxicity was demonstrated. In vitro study shows the capacity of several wild NDV strains to lyse tumor cell lines. Two strains of them have significant strong oncolytic activity on human tumor cells of various histogenesis. Recent work in our research also describes the results of in vivo experiments. One of them consists of comparing the efficacy of NDV strain to exhibit specific oncolytic activity in C57Bl/6 mice on subcutaneous murine tumors (LLC and B16) . Our results show that both intravenous and intratumoral injections with multiple doses of wild NDV strain lead to survival prolongation in B16- and LLC-bearing mice and prevent tumor development. We demonstrate antitumor activity of NDV/Altai/pigeon/770/2011 against murine KREBS-2 solid tumor in preclinical model on immunocompetent BALB/c mice. Recently we have demonstrated that NDV/Altai/pigeon/770/2011 can destroy murine KREBS-2 cells in vitro. Moreover, in pilot study we have shown that intratumoral NDV injections decrease of tumor volume and result in complete regression of KREBS-2 tumor in MRI images. Here we test intratumoral administration of NDV and show suppression of Krebs-2 tumor growth in intramuscularly allograft model (2.6-fold less size that in untreated group). Importantly, spread of the virus causes significant tumor necrosis in Krebs-2 tumors. By 20 days after virotherapy, widespread necrosis of NDV-treated tumor is observed. We describe that the vast fields of necrosis in NDV-treated group are the results of formation of ischemic foci in tumor tissue with the rapid development of tumor node and slow neoangiogenesis. Histological examinations and morphometric analysis of tumors in NDV-treated and control groups show that the number of blood vessels including the newly formed in the untreated group is significantly higher than in the experimental group. Immunohistochemical staining (CD34, VEGFR) shows that blood vessels in tumor tissue is strongly reduced to 20 days post-treatment and neoangiogenesis progresses in untreated tumor tissue. Thus, results suggest that vascular disruption in the NDV-treated group indicates the virus ability to directly or indirectly affect tumor angiogenesis and regulate tissue trophism in that way. Understanding how and in which step this effect occurs may provide capacity to use oncolytic NDV strains for therapeutic benefit.
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Abstract: Oncolytic virotherapy on its own has numerous drawbacks, including an inability of the virus to actively target tumor cells and systemic toxicities at the high doses necessary to effectively treat tumors. Addition of immune cell-based carriers of oncolytic viruses holds promise as a technique in which oncolytic virus can be delivered directly to tumors in smaller and less toxic doses. Interestingly, the cell carriers themselves have also demonstrated antitumor effects, which can be augmented further by tailoring the appropriate oncolytic virus to the appropriate cell type. This review discusses the multiple factors that go into devising an effective, cell-based delivery system for oncolytic viruses. Keywords: oncolytic virus, cell carrier, immune cells, cancer therapy, myeloid-derived suppressor cells
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Objective: Oncolytic viruses delivered through intravenous injection trend to be eliminated by immune system and fail to exert anti-tumor activity. Several studies have shown that oncolytic viruses can be loaded into cells without losing the biological activity of either virus or cell carrier. Such packaging can significantly protect the viruses from immune-mediated eradication of virus. Moreover, using cell carriers targeting tumor cells, biological properties associated with tumor or the anatomical location of the tumor could precisely deliver the virus to the tumor site and exert the anti-tumor efficacy of oncolytic virus. This review discusses the mechanisms of cell carriers loading oncolytic virus in the treatment of cancer. DOI:10.3781/j.issn.1000-7431.2011.01.018
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Oncolytic virotherapy represents an emerging modality with tremendous promise for cancer treatment. Among various oncolytic virues,oncolytic herpes simplex virus is one of the most widely explored agents and shows significant anti tumor activity.In this review,we mainly discuss the advantages of oncolytic HSV,the principles of HSV genetic manipulation,the strategies of oncolytic HSV development and targeting,the ad- vances and challenges of oncolytic HSV in cancer therapy.
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Various studies are being conducted on oncolytic virotherapy which one of the mechanisms is mediating interferon (IFN) production by it exerts antitumor effects. The antiviral effect of IFN itself has a negative impact on the inhibition of oncolytic virus or tumor eradication. Therefore, it is very critical to understand the mechanism of IFN regulation by oncolytic viruses, and to define its mechanism is of great significance for improving the antitumor effect of oncolytic viruses. This review focuses on the regulatory mechanisms of IFNs by various oncolytic viruses and their combination therapies. In addition, the exerting and the producing pathways of IFNs are briefly summarized, and some current issues are put forward.
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Oncolytic viruses have been seriously considered for glioma therapy over the last 20 years. The oncolytic activity of several oncolytic strains has been demonstrated against human glioma cell lines and in in vivo xenotransplant models. So far, four of these stains have additionally completed the first phase I/II trials in relapsed glioma patients. Though safety and feasibility have been demonstrated, therapeutic efficacy in these initial trials, when described, was only minor. The role of the immune system in oncolytic virotherapy for glioma remained much less studied until recent years. When investigated, the immune system, adept at controlling viral infections, is often hypothesized to be a strong hurdle to successful oncolytic virotherapy. Several preclinical studies have therefore aimed to improve oncolytic virotherapy efficacy by combining it with immune suppression or evasion strategies. More recently however, a new paradigm has developed in the oncolytic virotherapy field stating that oncolytic virus-mediated tumor cell death can be accompanied by elicitation of potent activation of innate and adaptive anti-tumor immunity that greatly improves the efficacy of certain oncolytic strains. Therefore, it seems the three-way interaction between oncolytic virus, tumor and immune system is critical to the outcome of antitumor therapy. In this review we discuss the studies which have investigated how the immune system and oncolytic viruses interact in models of glioma. The novel insights generated here hold important implications for future research and should be incorporated into the design of novel clinical trials.
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This chapter contains sections titled: Introduction Oncolytic Viruses Targeting HSV to Cancer Cells Combination Therapy Involving the Oncolytic HSV Virus Clinical Trials with Oncolytic HSV Current Limitations of Oncolytic Virotherapy Conclusions and Future Perspectives Acknowledgments References
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Central to the development of oncolytic virotherapies for cancer will be a better understanding of the parameters that influence the outcome of virotherapy to treat disseminated cancer by i.v. administration versus regional disease by local treatment. Intratumoral administration of 01/PEME, an oncolytic adenovirus, required approximately 1000-fold less dose than i.v. administration to induce similar tumor growth inhibition. Despite the short (<10 min) circulating half-life of the virus DNA, we could monitor virus distribution to the tumor site and observed virus replication by >1000-fold increase in virus DNA copies over time. There were doses of 01/PEME for which the virus DNA concentration in the tumor increased over time but did not result in antitumor efficacy. Oncolytic virus replication at a tumor site may not be a relevant indication of antitumor efficacy. Efficient distribution to the tumor site may be one of the most critical parameters for antitumor efficacy with oncolytic virotherapy.
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