Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma

Errington, Fiona; White, C. L.; Twigger, Katie; Rose, Ailsa; Scott, Karen J.; Steele, Lynette P.; Ilett, Elizabeth J.; Prestwich, R.; Hs, Pandha; Coffey, Matthew; Selby, Peter J.; Vile, Richard G.; Harrington, Kevin; Melcher, Alan

doi:10.1038/gt.2008.58

Cited by 92 publications

(104 citation statements)

References 56 publications

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“…Consistent with our findings in human melanoma lines (8), where reovirus-induced cytotoxicity of human melanoma cell lines was reversed with the addition of a pan-caspase inhibitor ZVAD, when B16.F10 cells were treated in combination with cisplatin, partial reversal was observed, suggesting that at least some of the treated cells were dying through reovirus-associated apoptotic death mechanisms, as cisplatin-induced apoptosis is not thought to be caspase dependent. Annexin V/PI staining indicated significant proportions of late apoptotic/necrotic cells rather than purely apoptotic cell death, which may explain the partial reversal of cytotoxicity with ZVAD inhibition.…”

Section: Discussionsupporting

confidence: 76%

“…Reovirus has been shown to cause tumor regression after intralesional injections in immunodeficient mice and after systemic administration in immunocompetent mice (4,5). In addition to the exploitation of oncogene signaling, reovirus activates the host immune response to potentially enhance antitumor responses through the efficient induction of type I IFNs (7) and local inflammatory responses generated by reovirusinfected tumor cells cause bystander toxicity against reovirusresistant tumor cells and activation of human myeloid dendritic cells (8). Several phase I clinical studies of intratumoral (i.t.)…”

mentioning

confidence: 99%

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Synergistic Effects of Oncolytic Reovirus and Cisplatin Chemotherapy in Murine Malignant Melanoma

Pandha

Heinemann

Simpson

et al. 2009

Clinical Cancer Research

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Purpose: To test combination treatment schedules of reovirus and cisplatin chemotherapy in human and murine melanoma cell lines and murine models of melanoma and to investigate the possible mechanisms of synergistic antitumor effects. Experimental Design: The effects of reovirus ± chemotherapy on in vitro cytotoxicity and viral replication were assessed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay and plaque assay. Interactions between agents were assessed by combination index analysis. Mode of cell death was assessed by Annexin V/propidium iodide fluorescence-activated cell sorting-based assays; gene expression profiling of single versus combination treatments was completed using the Agilent microarray system. Single agent and combination therapy effects were tested in vivo in two immunocompetent models of murine melanoma. Results: Variable degrees of synergistic cytotoxicity between live reovirus and several chemotherapy agents were observed in B16.F10 mouse melanoma cells, most significantly with cisplatin (combination index of 0.42 ± 0.03 at ED 50 ). Combination of cisplatin and reovirus exposure led to increased late apoptotic/necrotic cell populations. Cisplatin almost completely abrogated the inflammatory cytokine gene up-regulation induced by reovirus. Combination therapy led to significantly delayed tumor growth and improved survival in vivo (P < 0.0001 and P = 0.0003, respectively). Cisplatin had no effect on the humoral response to reovirus in mice. However, cisplatin treatment suppressed the cytokine and chemokine response to reovirus in vitro and in vivo. Conclusion: The combination of reovirus and several chemotherapeutic agents synergistically enhanced cytotoxicity in human and murine melanoma cell lines in vitro and murine tumors in vivo. The data support the current reovirus/chemotherapy combination phase I clinical studies currently ongoing in the clinic. (Clin Cancer Res 2009; 15(19):6158-66)

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Section: Discussionsupporting

confidence: 76%

mentioning

confidence: 99%

Synergistic Effects of Oncolytic Reovirus and Cisplatin Chemotherapy in Murine Malignant Melanoma

Pandha

Heinemann

Simpson

et al. 2009

Clinical Cancer Research

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“…A variety of oncolytic viruses have been investigated in phase I to III clinical trials (2). In contrast to immortalized cell lines, primary human tumor samples have been found to be relatively resistant to direct viral oncolysis (3–6). Therefore, in a clinical context, the direct oncolytic activity of these agents is likely to be more limited than suggested by experimental models.…”

mentioning

confidence: 99%

Immune-Mediated Antitumor Activity of Reovirus Is Required for Therapy and Is Independent of Direct Viral Oncolysis and Replication

Prestwich

Ilett

Errington

et al. 2009

Clinical Cancer Research

152

140

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Purpose Reovirus is a naturally occurring oncolytic virus in clinical trials. Although tumor infection by reovirus can generate adaptive antitumor immunity, its therapeutic importance versus direct viral oncolysis is undefined. This study addresses the requirement for viral oncolysis and replication, and the relative importance of antitumor immunity and direct oncolysis in therapy. Experimental Design Nonantigen specific T cells loaded with reovirus were delivered i.v. to C57BL/6 and severe combined immunodeficient mice bearing lymph node and splenic metastases from the murine melanoma, B16ova, with assessment of viral replication, metastatic clearance by tumor colony outgrowth, and immune priming. Human cytotoxic lymphocyte priming assays were done with dendritic cells loaded with Mel888 cells before the addition of reovirus. Results B16ova was resistant to direct oncolysis in vitro, and failed to support reovirus replication in vitro or in vivo. Nevertheless, reovirus purged lymph node and splenic metastases in C57BL/6 mice and generated antitumor immunity. In contrast, reovirus failed to reduce tumor burden in severe combined immunodeficient mice bearing either B16ova or reovirus-sensitive B16tk metastases. In the human system, reovirus acted solely as an adjuvant when added to dendritic cells already loaded with Mel888, supporting priming of specific antitumor cytotoxic lymphocyte, in the absence of significant direct tumor oncolysis; UV-treated nonreplicating reovirus was similarly immunogenic. Conclusion The immune response is critical in mediating the efficacy of reovirus, and does not depend upon direct viral oncolysis or replication. The findings are of direct relevance to fulfilling the potential of this novel anticancer agent.

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“…During studies on basic reovirus biology, reovirus was discovered to possess an intrinsic specificity toward cancer cells over normal cells (11)(12)(13)(14)(15)(16)(17). Reovirus shows potent antitumor activity in a wide assortment of in vivo cancer models (18)(19)(20)(21)(22) and is being examined in numerous phase I/II and III human clinical trials (23)(24)(25)(26)(27)(28)(29)(30). All trials currently use the reovirus serotype 3 (T3) Dearing strain in its wild-type form (here referred to as T3wt).…”

mentioning

confidence: 99%

Reduction of Virion-Associated σ1 Fibers on Oncolytic Reovirus Variants Promotes Adaptation toward Tumorigenic Cells

Mohamed

Teicher

Haefliger

et al. 2015

J Virol

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Wild-type mammalian orthoreovirus serotype 3 Dearing (T3wt) is nonpathogenic in humans but preferentially infects and kills cancer cells in culture and demonstrates promising antitumor activity in vivo. Using forward genetics, we previously isolated two variants of reovirus, T3v1 and T3v2, with increased infectivity toward a panel of cancer cell lines and improved in vivo oncolysis in a murine melanoma model relative to that of T3wt. Our current study explored how mutations in T3v1 and T3v2 promote infectivity. Reovirions contain trimers of 1, the reovirus cell attachment protein, at icosahedral capsid vertices. Quantitative Western blot analysis showed that purified T3v1 and T3v2 virions had ϳ2-and 4-fold-lower levels of 1 fiber than did T3wt virions. Importantly, using RNA interference to reduce 1 levels during T3wt production, we were able to generate wild-type reovirus with reduced levels of 1 per virion. As 1 levels were reduced, virion infectivity increased by 2-to 5-fold per cellbound particle, demonstrating a causal relationship between virion 1 levels and the infectivity of incoming virions. During infection of tumorigenic L929 cells, T3wt, T3v1, and T3v2 uncoated the outer capsid proteins 3 and 1C at similar rates. However, having started with fewer 1 molecules, a complete loss of 1 was achieved sooner for T3v1 and T3v2. Distinct from intracellular uncoating, chymotrypsin digestion, as a mimic of natural enteric infection, resulted in more rapid 3 and 1C removal, unique disassembly intermediates, and a rapid loss of infectivity for T3v1 and T3v2 compared to T3wt. Optimal infectivity toward natural versus therapeutic niches may therefore require distinct reovirus structures and 1 levels. IMPORTANCEWild-type reovirus is currently in clinical trials as a potential cancer therapy. Our molecular studies on variants of reovirus with enhanced oncolytic activity in vitro and in vivo now show that distinct reovirus structures promote adaptation toward cancer cells and away from conditions that mimic natural routes of infection. Specifically, we found that reovirus particles with fewer molecules of the cell attachment protein 1 became more infectious toward transformed cells. Reduced 1 levels conferred a benefit to incoming particles only, resulting in an earlier depletion of 1 and a higher probability of establishing productive infection. Conversely, reovirus variants with fewer 1 molecules showed reduced stability and infectivity and distinct disassembly when exposed to conditions that mimic natural intestinal proteolysis. These findings support a model where the mode of infection dictates the precise optimum of reovirus structure and provide a molecular rationale for considering alternative reovirus structures during oncolytic therapy. M ammalian orthoreovirus (reovirus) is a nonenveloped, icosahedral virus in the Reoviridae family (1). Reovirus is nonpathogenic in humans and has long served as a safe model system for understanding icosahedral virus structure and replication. Although reovirus encodes...

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Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma

Cited by 92 publications

References 56 publications

Synergistic Effects of Oncolytic Reovirus and Cisplatin Chemotherapy in Murine Malignant Melanoma

Synergistic Effects of Oncolytic Reovirus and Cisplatin Chemotherapy in Murine Malignant Melanoma

Immune-Mediated Antitumor Activity of Reovirus Is Required for Therapy and Is Independent of Direct Viral Oncolysis and Replication

Reduction of Virion-Associated σ1 Fibers on Oncolytic Reovirus Variants Promotes Adaptation toward Tumorigenic Cells

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