Browsing by Subject "Oncolytic adenovirus"

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    Docetaxel Increases Antitumor Efficacy of Oncolytic Prostate-Restricted Replicative Adenovirus by Enhancing Cell Killing and Virus Distribution
    (Wiley, 2010) Li, Xiong; Liu, Youhong; Tang, Yong; Roger, Phipps; Jeng, Meei-Huey; Kao, Chinghai; Urology, School of Medicine
    Background: We explored multiple molecular mechanisms of the combination of docetaxel and an oncolytic prostate-restricted replication competent adenovirus (Ad) (PRRA) in advanced prostate cancer (PCa) models. The combinational therapy has potential to overcome the therapeutic limitations of poor virus distribution inside solid tumors. Methods: We evaluated the effect of docetaxel on the antitumor efficacy and efficiency of virus transduction, transgene expression and virus distribution of PRRA in a prostate-specific antigen/prostate-specific membrane antigen-positive tumor xenograft model. We also evaluated the effect of docetaxel on apoptosis induction, cell killing and the efficiency of transgene expression and virus replication in vitro. Results: Tumor growth inhibition was significantly enhanced when docetaxel was administrated before intratumor injection of PRRA. In vivo dual-photon microscopy and ex vivo fluorescence microscopy and immunohistochemistry showed that docetaxel increased transgene expression and expanded virus distribution. The combination of docetaxel and PRRA also increased cell apoptosis. In vitro, docetaxel significantly increased cell killing in PRRA-treated PCa cells. Docetaxel significantly increased Ad-mediated trangene expression independent of Ad binding receptors and replication capability. Docetaxel increased the activity of cytomegalovirus (CMV) promoter but not of a chimeric prostate-specific enhancer, resulting in higher transgene expression. The enhanced CMV promoter activity resulted from activation of p38 mitogen-activated protein kinase (MAPK) because inhibition of p38 MAPK blocked the docetaxel-induced increase in CMV promoter activity. Conclusions: Combining docetaxel with an oncolytic PRRA improved therapeutic potential by expanding virus distribution and enhancing cell apoptosis and killing. These studies suggested a novel mechanism for enhancing the effect of therapeutic genes delivered by a PRRA.
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    LyP-1-Modified Oncolytic Adenoviruses Targeting Transforming Growth Factor β Inhibit Tumor Growth and Metastases and Augment Immune Checkpoint Inhibitor Therapy in Breast Cancer Mouse Models
    (Mary Ann Liebert, Inc., 2020-08) Xu, Weidong; Yang, Yuefeng; Hu, Zebin; Head, Maria; Mangold, Kathy A.; Sullivan, Megan; Wang, Edward; Saha, Poornima; Gulukota, Kamalakar; Helseth, Donald L., Jr.; Guise, Theresa; Prabhkar, Bellur S.; Kaul, Karen; Schreiber, Hans; Seth, Prem; Medicine, School of Medicine
    We report here the development of oncolytic adenoviruses (Ads) that have reduced toxicity, enhanced tumor tropism, produce strong antitumor response, and can overcome resistance to immune checkpoint inhibitor therapy in breast cancer. We have shown that LyP-1 receptor (p32) is highly expressed on the surface of breast cancer cells and tumors from cancer patients, and that increased stromal expression of transforming growth factor β-1 (TGFβ-1) is associated with triple-negative breast cancer. Therefore, we constructed oncolytic Ads, AdLyp.sT and mHAdLyp.sT, in which the p32-binding LyP-1 peptide was genetically inserted into the adenoviral fiber protein. Both AdLyp.sT and mHAdLyp.sT express sTGFβRIIFc, a TGFβ decoy that can inhibit TGFβ pathways. mHAdLyp.sT is an Ad5/48 chimeric hexon virus in which hypervariable regions (HVRs 1–7) of Ad5 are replaced with the corresponding Ad48 HVRs. AdLyp.sT and mHAdLyp.sT exhibited better binding, replication, and produced higher sTGFβRIIFc protein levels in breast cancer cell lines compared with Ad.sT or mHAd.sT control viruses without LyP-1 peptide modification. Systemic delivery of mHAdLyp.sT in mice resulted in reduced hepatic/systemic toxicity compared with Ad.sT and AdLyp.sT. Intravenous delivery of AdLyp.sT and mHAdLyp.sT elicited a strong antitumor response in a human MDA-MB-231 bone metastasis model in mice, as indicated by bioluminescence imaging, radiographic tumor burden, serum TRACP 5b and calcium, and body weight analyses. Furthermore, intratumoral delivery of AdLyp.sT in 4T1 model in immunocompetent mice inhibited tumor growth and metastases, and augmented anti-PD-1 and anti-CTLA-4 therapy. Based on these studies, we believe that AdLyp.sT and mHAdLyp.sT can be developed as potential targeted immunotherapy agents for the treatment of breast cancer.