Oncolytic efficacy of thymidine kinase-deleted vaccinia virus strain Guang9

Deng, Lili; Fan, Jianling; Ding, Yuedi; Zhang, Jue; Zhou, Bin; Zhang, Yi; Huang, Biao

doi:10.18632/oncotarget.17125

Cited by 32 publications

(20 citation statements)

References 45 publications

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“…Here, for the first time we report the genomic sequence analysis of CF33 and the oncolytic properties of J2R-deleted CF33 in lung cancer model using both xenograft and syngeneic tumor models. In accordance with other published studies on the cancer specificity of J2R-deleted poxviruses, CF33-GFP demonstrated higher replication and cell killing ability in cancer cells compared to normal cells in vitro [9,34,35]. Furthermore, like several other OVs, CF33-GFP was found to induce markers of ICD in lung cancer cells, in vitro [36][37][38].…”

Section: Discussionsupporting

confidence: 90%

A chimeric poxvirus with J2R (thymidine kinase) deletion shows safety and anti-tumor activity in lung cancer models

et al. 2019

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Oncolytic viruses have shown excellent safety profiles in preclinical and clinical studies; however, in most cases therapeutic benefits have been modest. We have previously reported the generation of a chimeric poxvirus (CF33), with significantly improved oncolytic characteristics, through chimerization among different poxviruses. Here we report the sequence analysis of CF33 and oncolytic potential of a GFP-encoding CF33 virus (CF33-GFP) with a J2R deletion in lung cancer models. Replication of CF33-GFP and the resulting cytotoxicity were higher in cancer cell lines compared to a normal cell line, in vitro. After infection with virus, cancer cells expressed markers for immunogenic cell death in vitro. Furthermore, CF33-GFP was safe and exerted potent anti-tumor effects at a dose as low as 1000 plaque forming units in both virus-injected and un-injected distant tumors in A549 tumor xenograft model in mice. Likewise, in a syngeneic model of lung cancer in mice, the virus showed significant anti-tumor effect and was found to increase tumor infiltration by CD8+ T cells. Collectively, these data warrant further investigation of this novel chimeric poxvirus for its potential use as a cancer bio-therapeutic.

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Section: Discussionsupporting

confidence: 90%

A chimeric poxvirus with J2R (thymidine kinase) deletion shows safety and anti-tumor activity in lung cancer models

et al. 2019

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“…Notably, suppression of ISG responses and restoration of postreplicative-viralprotein production did not reach the levels observed for WT virus, likely due to lower expression of F17 by the iF17-R virus. While the absence of TK has been shown to reduce virus replication in normal cells in vivo (99), studies suggest there is little requirement for TK in cultured cells, including resting normal cells (100,101). However, although we cannot completely rule out a contribution from TK to overall virus replication in the iF17 mutant background, our data clearly show that F17 mediates mTOR activation and reveal a dose-dependent correlation between F17 expression and the extent of ISG suppression, as well as viral-protein production across all three viruses, regardless of genetic background.…”

Section: Fig 3 Effects Of Poxvirus Infection and Mtor Inhibition On Mmentioning

confidence: 99%

mTOR Dysregulation by Vaccinia Virus F17 Controls Multiple Processes with Varying Roles in Infection

Meade

King

Munger

et al. 2019

J Virol

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Despite producing enormous amounts of cytoplasmic DNA, poxviruses continue to replicate efficiently by deploying an armory of proteins that counter host antiviral responses at multiple levels. Among these, poxvirus protein F17 dysregulates the host kinase mammalian target of rapamycin (mTOR) to prevent the activation of stimulator of interferon genes (STING) expression and impair the production of interferon-stimulated genes (ISGs). However, the host DNA sensor(s) involved and their impact on infection in the absence of F17 remain unknown. Here, we show that cyclic-di-GMP-AMP (cGAMP) synthase (cGAS) is the primary sensor that mediates interferon response factor (IRF) activation and ISG responses to vaccinia virus lacking F17 in both macrophages and lung fibroblasts, although additional sensors also operate in the latter cell type. Despite this, ablation of ISG responses through cGAS or STING knockout did not rescue defects in late-viral-protein production, and the experimental data pointed to other functions of mTOR in this regard. mTOR adjusts both autophagic and protein-synthetic processes to cellular demands. No significant differences in autophagic responses to wild-type or F17 mutant viruses could be detected, with autophagic activity differing across cell types or states and exhibiting no correlations with defects in viral-protein accumulation. In contrast, results using transformed cells or altered growth conditions suggested that late-stage defects in protein accumulation reflect failure of the F17 mutant to deregulate mTOR and stimulate protein production. Finally, rescue approaches suggest that phosphorylation may partition F17’s functions as a structural protein and mTOR regulator. Our findings reveal the complex multifunctionality of F17 during infection. IMPORTANCE Poxviruses are large, double-stranded DNA viruses that replicate entirely in the cytoplasm, an unusual act that activates pathogen sensors and innate antiviral responses. In order to replicate, poxviruses therefore encode a wide range of innate immune antagonists that include F17, a protein that dysregulates the kinase mammalian target of rapamycin (mTOR) to suppress interferon-stimulated gene (ISG) responses. However, the host sensor(s) that detects infection in the absence of F17 and its precise contribution to infection remains unknown. Here, we show that the cytosolic DNA sensor cGAS is primarily responsible for activating ISG responses in biologically relevant cell types infected with a poxvirus that does not express F17. However, in line with their expression of ∼100 proteins that act as immune response and ISG antagonists, while F17 helps suppress cGAS-mediated responses, we find that a critical function of its mTOR dysregulation activity is to enhance poxvirus protein production.

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“…34 Recombinant VACV has shown therapeutic effects in several murine tumor models, including those of glioblastoma, pancreatic cancer, and melanoma. [35][36][37][38] Interestingly, we found that both WT and recombinant VACV were less replicative in the murine triple-negative breast cancer (TNBC) cell line 4T1, which shows high levels of TTP, 39 both in vitro and in vivo. Furthermore, TNBC cells from different species differ in terms of TTP expression, which affects the replication of recombinant VACV.…”

Section: Discussionmentioning

confidence: 94%

<p>The Ectopic Expression of SurvivinT34A and FilC Can Enhance the Oncolytic Effects of Vaccinia Virus in Murine Gastric Cancer</p>

Wang¹,

Luo²,

Sun³

et al. 2020

OTT

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Background/Aims: Anti-tumor vaccines have been shown to be effective in cancer therapeutics ever since the anti-HPV vaccine was developed. Compared to conventional chemotherapy, anti-tumor vaccines can specifically target cancer cells and they have lower side effects. We developed a recombinant vaccinia virus (VACV) (Western Reserve) WR strain, and we tested its anti-tumor effects in an animal model. Methods: A recombinant VACV WR strain expressing mutant survivin T34A (SurT34A) and FilC was constructed and validated. Its oncolytic effect was tested in vitro using a CCK-8 assay, and its tolerance and anti-tumor effects were tested in a murine gastric cancer model. The proportion of lymphocytes in the spleen and tumor was determined after antibody-mediated immuno-depletion. Results: The recombinant VACV showed a stronger replication ability in tumor cells, and it was safe in vivo, even at high doses. The combination of vv-SurT34A and vv-FilC resulted in a stronger anti-tumor effect compared to either construct alone. However, the inhibitory effect of vv-SurT34A was stronger than the combination. The recombinant VACV activated the host immune response, as indicated by lymphocyte infiltration in the spleen and tumor tissues. Conclusion: The recombinant VACV WR strain expressing SurT34A and FilC is a safe and effective anti-tumor vaccine.

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Oncolytic efficacy of thymidine kinase-deleted vaccinia virus strain Guang9

Cited by 32 publications

References 45 publications

A chimeric poxvirus with J2R (thymidine kinase) deletion shows safety and anti-tumor activity in lung cancer models

A chimeric poxvirus with J2R (thymidine kinase) deletion shows safety and anti-tumor activity in lung cancer models

mTOR Dysregulation by Vaccinia Virus F17 Controls Multiple Processes with Varying Roles in Infection

<p>The Ectopic Expression of SurvivinT34A and FilC Can Enhance the Oncolytic Effects of Vaccinia Virus in Murine Gastric Cancer</p>

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