Innate Immune Defense Defines Susceptibility of Sarcoma Cells to Measles Vaccine Virus-Based Oncolysis

Berchtold, Susanne; Lampe, Johanna W.; Weiland, Timo; Smirnow, Irina; Schleicher, Sabine; Handgretinger, Rupert; Kopp, Hans‐Georg; Reiser, J; Stubenrauch, Frank; Mayer, Nóra; Malek, Nisar P.; Bitzer, Michael; Lauer, Ulrich M.

doi:10.1128/jvi.02106-12

Cited by 54 publications

(61 citation statements)

References 46 publications

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“…Intratumoral administration also can lead to complement- and antibody-mediated destruction of the OV. In addition, intracellular and microenvironmental antiviral defense responses in infected tumor cells also can greatly limit the magnitude of OV replication (25–31). Finally, innate immune cells can rapidly respond to an administered OV further limiting its survival and that of OV-infected tumor cells (32–35).…”

Section: Innate Immunitymentioning

confidence: 99%

Oncolytic Viruses and Their Application to Cancer Immunotherapy

Rabkin

2014

Cancer Immunology Research

319

286

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Oncolytic viruses (OVs) selectively replicate in and kill cancer cells, and spread within the tumor, while not harming normal tissue. In addition to this direct oncolytic activity, OVs are also very effective at inducing immune responses to themselves and to the infected tumor cells. OVs encompass a broad diversity of DNA and RNA viruses that are naturally cancer-selective or can be genetically-engineered. OVs provide a diverse platform for immunotherapy; they act as in situ vaccines, and can be armed with immune modulatory transgenes or combined with other immunotherapies. However, the interactions of OVs with the immune system may affect therapeutic outcomes in opposing fashions: negatively by limiting virus replication and/or spread, or positively by inducing antitumor immune responses. Many aspects of the OV-tumor/host interaction are important in delineating the effectiveness of therapy; they include: (i) innate immune responses and the degree of inflammation induced, (ii) types of virus-induced cell death, (iii) inherent tumor physiology, such as infiltrating and resident immune cells, vascularity/hypoxia, lymphatics, and stromal architecture, and (iv) tumor cell phenotype, including alterations in IFN signaling, oncogenic pathways, cell surface immune markers (MHC, co-stimulatory, NK receptors), and the expression of immunosuppressive factors. Recent clinical trials with a variety of OVs, especially those expressing GM-CSF, have demonstrated efficacy and induction of antitumor immune responses in the absence of significant toxicity. Manipulating the balance between anti-virus and antitumor responses, often involving overlapping immune pathways, will be critical to the clinical success of OVs.

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Section: Innate Immunitymentioning

confidence: 99%

Oncolytic Viruses and Their Application to Cancer Immunotherapy

Rabkin

2014

Cancer Immunology Research

319

286

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“…Therefore, this in vitro study has set out to provide a systematic data basis for the design of potential future prodrug application regimens, focusing for the time being on our prototypic measles vaccine virus vector MeV-SCD, which encodes a fusion protein consisting of yCD and yUPRT (Erbs et al, 2000;Berchtold et al, 2013). Of note, we also particularly looked for potential interferences of the prodrugs enzymatically converted into nucleoside analogs, thereby potentially impairing virotherapeutic replication.…”

Section: Discussionmentioning

confidence: 99%

Pulsed Versus Continuous Application of the Prodrug 5-Fluorocytosine to Enhance the Oncolytic Effectiveness of a Measles Vaccine Virus Armed with a Suicide Gene

Yurttas

Berchtold

Malek

et al. 2014

Human Gene Therapy Clinical Development

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Oncolytic virotherapy with measles vaccine virus (MeV) already has been demonstrated to be safe. However, early clinical results pointed out the necessity for an enhancement of oncolytic effectiveness of MeV-based virotherapeutics. In our work, we are developing an armed measles vaccine virus (MeV-SCD) encoding a suicide fusion gene of yeast cytosine deaminase/uracil phosphoribosyltransferase, converting the nontoxic prodrug 5-fluorocytosine (5-FC) to the chemotherapeutic drug 5-fluorouracil (5-FU). To preclinically investigate what an optimal prodrug-assisted therapeutic regimen might look like, we added 5-FC at various time points after infection with MeV-SCD and either let the prodrug remain in the tumor cell culture medium continuously for various time periods ("continuous" 5-FC application) or applied it only temporarily for defined shorter periods of time ("pulsed" 5-FC application); we also varied the time point at which 5-FC was added after infection with MeV-SCD. As a result, addition of the prodrug at early times postinfection (e.g., at 3 hr postinfection) was found to be inferior concerning the overall oncolytic effectiveness when compared with addition of 5-FC at later time points (e.g., at 24 hr postinfection). Next, oncolytic effectiveness was found to correlate positively with the overall duration of incubation of MeV-infected tumor cells with 5-FC. Of note, this was true despite our finding that addition of the prodrug could also exert an inhibitory effect on the generation of infectious progeny viral particles, that is, on virus replication. These findings should be helpful for the rational design of further trials (preclinical, clinical) using suicide gene armed virotherapeutics, such as MeV-SCD.

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“…Activation of the JAK/STAT pathway and ISG expression limits other oncolytic viruses including vesicular stomatitis virus (13, 19,22, 23, 25), measles virus (20), Newcastle Disease virus (21), respiratory syncytial virus (26), Semliki Forest virus (27), and adenovirus (28, 29). In several of these studies inhibitors of JAK/STAT1 signaling enhanced viral productivity (19, 22,23, 25, 27).…”

Section: Discussionmentioning

confidence: 99%

STAT1 and NF-κB Inhibitors Diminish Basal Interferon-Stimulated Gene Expression and Improve the Productive Infection of Oncolytic HSV in MPNST Cells

Jackson

Markert

et al. 2016

Molecular Cancer Research

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Interferon stimulated genes (ISGs) encode diverse proteins that mediate intrinsic antiviral resistance in infected cells. Here it was hypothesized that malignant peripheral nerve sheath tumor (MPNST) cells resist the productive infection of oncolytic herpes simplex virus (oHSV) through activation of the JAK/STAT1 pathway and resultant upregulation of ISGs. Multiple human and mouse MPNST cells were used to explore the relationship between STAT1 activation and the productive infection of Δγ-134.5 oHSVs. STAT1 activation in response to oHSV infection was found to associate with diminished Δγ-134.5 oHSVs replication and spread. Multi-day pre-treatment, but not co-treatment, with a JAK inhibitor significantly improved viral titer and spread. ISG expression was found to be elevated prior to infection and downregulated when treated with the inhibitor, suggesting that the JAK/STAT1 pathway is active prior to infection. Conversely, upregulation of ISG expression in normally permissive cells significantly decreased oHSV productivity. Finally, a possible link between NFκB pathway activation and ISG expression was established through the expression of inhibitor of kB (IκB) which decreased basal STAT1 transcription and ISG expression. These results demonstrate that basal ISG expression prior to infection contributes to the resistance of Δγ-134.5 oHSVs in MPNST cells. Implications While cancer-associated ISG expression has been previously reported to impart resistance to chemotherapy and radiotherapy, these data show that basal ISG expression also contributes to oncolytic HSV resistance.

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Innate Immune Defense Defines Susceptibility of Sarcoma Cells to Measles Vaccine Virus-Based Oncolysis

Abstract: The oncolytic potential of measles vaccine virus (MeV) has been demonstrated in several tumor entities. Here, we investigated the susceptibility of eight sarcoma cell lines to MeV-mediated oncolysis and found five to be susceptible, whereas three proved to be resistant. In the

Cited by 54 publications

References 46 publications

Oncolytic Viruses and Their Application to Cancer Immunotherapy

Oncolytic Viruses and Their Application to Cancer Immunotherapy

Pulsed Versus Continuous Application of the Prodrug 5-Fluorocytosine to Enhance the Oncolytic Effectiveness of a Measles Vaccine Virus Armed with a Suicide Gene

STAT1 and NF-κB Inhibitors Diminish Basal Interferon-Stimulated Gene Expression and Improve the Productive Infection of Oncolytic HSV in MPNST Cells

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