Reovirus-Mediated Cytotoxicity and Enhancement of Innate Immune Responses Against Acute Myeloid Leukemia

Hall, Kathryn; Scott, Karen J.; Rose, Ailsa; Desborough, Michael; Harrington, Kevin J.; Pandha, Hardev; Parrish, Christopher; Vile, Richard G.; Coffey, Matt; Bowen, David; Errington-Mais, Fiona; Melcher, Alan

doi:10.1089/biores.2012.0205

Cited by 24 publications

(18 citation statements)

References 57 publications

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“…In balancing the therapeutic and damaging effects some groups have suggested the possibility of early, transient immunosuppression to enhance viral replication, followed by a restoration of immune activity to harness the immunotherapeutic potential of OVT. However, the early, innate immune reactivity induced by OVT has also demonstrated to partake in the therapeutic benefit of the therapeutic approach, and could be important in the priming of further adaptive antitumor reactivity 92 ; 93 .…”

Section: Discussionmentioning

confidence: 99%

Immune Suppression during Oncolytic Virotherapy for High-Grade Glioma; Yes or No?

Koks

Vleeschouwer²,

Graf³

et al. 2015

J. Cancer

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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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Section: Discussionmentioning

confidence: 99%

Immune Suppression during Oncolytic Virotherapy for High-Grade Glioma; Yes or No?

Koks

Vleeschouwer²,

Graf³

et al. 2015

J. Cancer

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“…The surface protein Junctional Adhesion Molecule 1 (JAM-1) and in the central nervous system Negative Growth Regulatory Protein 1 (NGR1) are the cellular receptors responsible for RV entry in human cells (4, 5). The virus mediates its antitumor activity via induction of direct cytolysis, and activation of a tumor-directed immune response (6–8). …”

Section: Introductionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Enhance the Therapeutic Potential of Reovirus in Multiple Myeloma

Stiff

Caserta

Sborov

et al. 2016

Molecular Cancer Therapeutics

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Multiple myeloma (MM) remains incurable and the majority of patients die within 5 years of diagnosis. Reolysin, the infusible form of human reovirus (RV), is a novel viral oncolytic therapy associated with antitumor activity likely resulting from direct oncolysis and a virus-mediated antitumor immune response. Results from our phase I clinical trial investigating single agent Reolysin in patients with relapsed MM confirmed tolerability, but no objective responses were evident, likely because the virus selectively entered the MM cells but did not actively replicate. To date, the precise mechanisms underlying the RV infectious life cycle and its ability to induce oncolysis in patients with MM remain unknown. Here we report that Junctional Adhesion Molecule 1 (JAM-1), the cellular receptor for RV, is epigenetically regulated in MM cells. Treatment of MM cells with clinically relevant histone deacetylase inhibitors (HDACi) results in increased JAM-1 expression as well as increased histone acetylation and RNA polymerase II recruitment to its promoter. Further, our data indicate that the combination of Reolysin with HDACi, potentiates RV killing activity of MM cells in vitro and in vivo. This study provides the molecular basis to use these agents as therapeutic tools to increase the efficacy of RV therapy in MM.

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“…In acute myeloid leukemia samples, reovirus infection induced secretion of the proinflammatory cytokine IFNa and the chemokine RANTES from the leukemic blasts and simultaneously activated NK cells and peripheral blood mononuclear cells (PBMC; ref. 35). Future work will clarify the mechanisms by which reovirus infection provokes an antitumor adaptive immune response.…”

Section: Mechanism Of Tumor Lysismentioning

confidence: 98%

Strategic Combinations: The Future of Oncolytic Virotherapy with Reovirus

Zhao

Chester

Rajasekaran

et al. 2016

Molecular Cancer Therapeutics

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The dominant cancer treatment modalities such as chemotherapy, radiotherapy, and even targeted kinase inhibitors and mAbs are limited by low efficacy, toxicity, and treatmentresistant tumor subclones. Oncolytic viral therapy offers a novel therapeutic strategy that has the potential to dramatically improve clinical outcomes. Reovirus, a double-stranded benign human RNA virus, is a leading candidate for therapeutic development and currently in phase III trials. Reovirus selectively targets transformed cells with activated Ras signaling pathways; Ras genes are some of the most frequently mutated oncogenes in human cancer and it is estimated that at least 30% of all human tumors exhibit aberrant Ras signaling. By targeting Rasactivated cells, reovirus can directly lyse cancer cells, disrupt tumor immunosuppressive mechanisms, reestablish multicellular immune surveillance, and generate robust antitumor responses. Reovirus therapy is currently being tested in combination with radiotherapy, chemotherapy, immunotherapy, and surgery. In this review, we discuss the current successes of these combinatorial therapeutic strategies and emphasize the importance of prioritizing combination oncolytic viral therapy as reovirus-based treatments progress in clinical development.

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Reovirus-Mediated Cytotoxicity and Enhancement of Innate Immune Responses Against Acute Myeloid Leukemia

Cited by 24 publications

References 57 publications

Immune Suppression during Oncolytic Virotherapy for High-Grade Glioma; Yes or No?

Immune Suppression during Oncolytic Virotherapy for High-Grade Glioma; Yes or No?

Histone Deacetylase Inhibitors Enhance the Therapeutic Potential of Reovirus in Multiple Myeloma

Strategic Combinations: The Future of Oncolytic Virotherapy with Reovirus

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