tetano
Editor, Senior Moderator
Citation: van Rikxoort M, Michaelis M, Wolschek M, Muster T, Egorov A, et al. (2012) Oncolytic Effects of a Novel Influenza A Virus Expressing Interleukin-15 from the NS Reading Frame. PLoS ONE 7(5): e36506. doi:10.1371/journal.pone.0036506
Marijke van Rikxoort1, Martin Michaelis1?, Markus Wolschek2, Thomas Muster2, Andrej Egorov2, Joachim Seipelt2, Hans Wilhelm Doerr1, Jindrich Cinatl Jr1*
1 Institut f?r Medizinische Virologie, Klinikum der Johann Wolfgang Goethe-Universit?t, Frankfurt am Main, Germany, 2 AVIR Green Hills Biotechnology, Vienna, Austria
Abstract Top
Oncolytic influenza A viruses with deleted NS1 gene (delNS1) replicate selectively in tumour cells with defective interferon response and/or activated Ras/Raf/MEK/ERK signalling pathway. To develop a delNS1 virus with specific immunostimulatory properties, we used an optimised technology to insert the interleukin-15 (IL-15) coding sequence into the viral NS gene segment (delNS1-IL-15). DelNS1 and delNS1-IL-15 exerted similar oncolytic effects. Both viruses replicated and caused caspase-dependent apoptosis in interferon-defective melanoma cells. Virus replication was required for their oncolytic activity. Cisplatin enhanced the oncolytic activity of delNS1 viruses. The cytotoxic drug increased delNS1 replication and delNS1-induced caspase-dependent apoptosis. Interference with MEK/ERK signalling by RNAi-mediated depletion or the MEK inhibitor U0126 did not affect the oncolytic effects of the delNS1 viruses. In oncolysis sensitive melanoma cells, delNS1-IL-15 (but not delNS1) infection resulted in the production of IL-15 levels ranging from 70 to 1140 pg/mL in the cell culture supernatants. The supernatants of delNS1-IL-15-infected (but not of delNS1-infected) melanoma cells induced primary human natural killer cell-mediated lysis of non-infected tumour cells. In conclusion, we constructed a novel oncolytic influenza virus that combines the oncolytic activity of delNS1 viruses with immunostimulatory properties through production of functional IL-15. Moreover, we showed that the oncolytic activity of delNS1 viruses can be enhanced in combination with cytotoxic anti-cancer drugs.
http://www.plosone.org/article/info...osone/PLoSONE+(PLoS+ONE+Alerts:+New+Articles)
Marijke van Rikxoort1, Martin Michaelis1?, Markus Wolschek2, Thomas Muster2, Andrej Egorov2, Joachim Seipelt2, Hans Wilhelm Doerr1, Jindrich Cinatl Jr1*
1 Institut f?r Medizinische Virologie, Klinikum der Johann Wolfgang Goethe-Universit?t, Frankfurt am Main, Germany, 2 AVIR Green Hills Biotechnology, Vienna, Austria
Abstract Top
Oncolytic influenza A viruses with deleted NS1 gene (delNS1) replicate selectively in tumour cells with defective interferon response and/or activated Ras/Raf/MEK/ERK signalling pathway. To develop a delNS1 virus with specific immunostimulatory properties, we used an optimised technology to insert the interleukin-15 (IL-15) coding sequence into the viral NS gene segment (delNS1-IL-15). DelNS1 and delNS1-IL-15 exerted similar oncolytic effects. Both viruses replicated and caused caspase-dependent apoptosis in interferon-defective melanoma cells. Virus replication was required for their oncolytic activity. Cisplatin enhanced the oncolytic activity of delNS1 viruses. The cytotoxic drug increased delNS1 replication and delNS1-induced caspase-dependent apoptosis. Interference with MEK/ERK signalling by RNAi-mediated depletion or the MEK inhibitor U0126 did not affect the oncolytic effects of the delNS1 viruses. In oncolysis sensitive melanoma cells, delNS1-IL-15 (but not delNS1) infection resulted in the production of IL-15 levels ranging from 70 to 1140 pg/mL in the cell culture supernatants. The supernatants of delNS1-IL-15-infected (but not of delNS1-infected) melanoma cells induced primary human natural killer cell-mediated lysis of non-infected tumour cells. In conclusion, we constructed a novel oncolytic influenza virus that combines the oncolytic activity of delNS1 viruses with immunostimulatory properties through production of functional IL-15. Moreover, we showed that the oncolytic activity of delNS1 viruses can be enhanced in combination with cytotoxic anti-cancer drugs.
http://www.plosone.org/article/info...osone/PLoSONE+(PLoS+ONE+Alerts:+New+Articles)