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    A bicistronic adenoviral vector carrying cytosine deaminase and GM-CSF genes significantly improves antitumor immunity and overall survival in colon cancer
    (Amer Assoc Cancer Research, 2018) Akbulut, Hakan; Çöleri, Arzu; Şahin, Günce; Tang, Yucheng; Deisseroth, Albert
    Background: Combination of cytotoxic treatments with immunotherapeutic agents seem more efficacious than using either strategy alone. Oncolytic viral vectors carrying immunostimulatory genes like GM-CSF have emerged as treatment options in various tumors. Previously, we have shown that combination of suicide gene therapy either with GM-CSF or vector-induced dendritic cells has significant anti-tumor efficacy. In the current study, we aimed to combine the cytotoxic effect of the suicide gene cytosine deaminase and the immunostimulatory effect of granulocyte macrophage colony stimulating factor in a single vector construct. Methods: We have constructed a bicistronic adenoviral vector carrying cytosine deaminase (CD) and granulocyte macrophage-colony stimulating factor (GM-CSF) genes combined with an IRES element and driven by CMV promoter (Ad-CMV-CDiresGMCSF). We tested the in vitro efficacy of the vector in various tumor cell lines and in a mouse model of colon cancer. Results: Our bicistronic vector Ad-CMV-CDiresGMCSF showed significant in-vitro cytotoxic effects on tumor cell lines similar to the vector carrying CD gene alone when 5-FC added. Likewise, the GM-CSF producing efficacy of the bicistronic vector was comparable to the vector carrying GM-CSF gene alone. In the syngeneic colon cancer model, the bicistronic vector carrying CD and GM-CSF genes yielded significant tumor shrinkage and overall survival when compared to the control suicide vector carrying CD gene alone. Accordingly, anti-tumor immune response parameters including CTL assay and immune cell infiltration of tumor tissue were significantly improved in the Ad-CMV-CDiresGMCSF vector treated group (p<0.01). Conclusions: The Ad-CMV-CDiresGMCSF vector construct suggests a potential for the treatment of established tumors by inducing significant tumor killing and tumor-specific immune response.
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    A bicistronic adenoviral vector carrying cytosine deaminase and granulocyte-macrophage colony-stimulating factor increases the therapeutic efficacy of cancer gene therapy
    (Mary Ann Liebert, Inc, 2019) Akbulut, Hakan; Çöleri, Arzu; Şahin, Günce; Tang, Yucheng; İçli, Fikri
    The combination of cytotoxic treatment modalities, including oncolytic viral gene therapies and immunotherapy, usually yields a synergistic effect. In the current study, a bicistronic adenoviral vector, Ad-CD-GMCSF, carrying the cytosine deaminase (CD) and granulocyte-macrophage colony-stimulating factor (GM-CSF) transcription units driven by a cytomegalovirus promoter was constructed, and the in vitro efficacy of the vector was tested in tumor cell lines and a syngeneic mouse model of colon cancer. The tumor cells infected with Ad-CD-GMCSF vector were found to produce a substantial amount of GM-CSF in tumor cell lines. Accordingly, the vector carrying CD and GM-CSF transcription units together induced a potent antitumor immunity with a significantly increased number of tumor-specific T cells and tumor-specific T-cell cytotoxicity (p < 0.001). The tumor growth rate of Ad-CD-GMCSF-treated mice was significantly lower when compared to the control and an adenoviral vector carrying only the CD transcription unit (Ad-CD; p < 0.05). Likewise, the median overall survival of the Ad-CD-GMCSF vector group was significantly higher than that of the control and Ad-CD groups (34.0 +/- 12.8 vs. 14.0 +/- 0.5 and 23.0 +/- 2.8 days, respectively; p < 0.001). In conclusion, along with its cytotoxic effect, the high immunostimulatory effect of the bicistronic Ad-CD-GMCSF vector has excellent potential in the treatment of cancers.