Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA306644 | ENA |
REPOSITORIES: ENA
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Project description:Human melanoma tumor cells (HS294T) and monocytes (THP-1) were infected with a double deleted (-VGF, -TK) oncolytic vaccinia virus expressing human DAI (DNA-dependent activator of interferon-regulatory factors). Total RNA was collected and gene expresson profiles were determined with Agilent microarray. An oncolytic vaccinia virus that does not express DAI was used to control the effect of DAI and uninfected cells (PBS treated) were used to control the effect of virus infection. In oncolytic virotherapy the ability of the virus to activate the immune system against tumors is nowadays generally understood to be a key mechanism in full eradication of cancer and for long-term anti-tumor effects. We armed an oncolytic vaccinia virus with DAI to increase the immunogenicity and the vaccine potency of the virus. The aim of this study was to study if the expression of DAI by a replicating vaccinia virus would alter the gene expression profile of infected cells and to study what are the differentially expressed genes.
2016-03-01 | GSE76208 | GEO
Project description:Human melanoma tumor cells (HS294T) and monocytes (THP-1) were infected with a double deleted (-VGF, -TK) oncolytic vaccinia virus expressing human DAI (DNA-dependent activator of interferon-regulatory factors). Total RNA was collected and gene expresson profiles were determined with Agilent microarray. An oncolytic vaccinia virus that does not express DAI was used to control the effect of DAI and uninfected cells (PBS treated) were used to control the effect of virus infection. In oncolytic virotherapy the ability of the virus to activate the immune system against tumors is nowadays generally understood to be a key mechanism in full eradication of cancer and for long-term anti-tumor effects. We armed an oncolytic vaccinia virus with DAI to increase the immunogenicity and the vaccine potency of the virus. The aim of this study was to study if the expression of DAI by a replicating vaccinia virus would alter the gene expression profile of infected cells and to study what are the differentially expressed genes. Three-condition experiment: vvdd-tdTomato-hDAI vs. vvdd-tdTomato vs. PBS treated cells. 2 cell lines: HS294T tumor cells and THP-1 monocytes. 3 biological replicates of virus infected cells per cell line and 2 uninfected replicates per cell line. HS294T and THP-1 cells were treated with vvdd-tdTomato-hDAI or vvdd-tdTomato control virus, or with PBS only to have an uninfected control. 16 hours after infection total RNA was extracted and whole genome gene pfofiles were analyzed and differentially expressed genes determined.
2016-03-01 | E-GEOD-76208 | biostudies-arrayexpress
Project description:Oncolytic viruses are complex biological agents that interact at multiple levels with both tumor and normal tissues. Anti-viral pathways induced by interferon are known to play a critical role in determining tumor cell sensitivity and normal cell resistance to infection with oncolytic viruses. Here we pursue a synthetic biology approach to identify methods that enhance anti-tumor activity of oncolytic viruses through suppression of IFN signaling. Based on the mathematical analysis of multiple strategies, we hypothesize that a positive feedback loop, established by virus-mediated expression of a soluble interferon-binding decoy receptor, increases tumor cytotoxicity without compromising normal cells. Oncolytic rhabodviruses engineered to express a secreted interferon antagonist have improved oncolytic potential in cellular cancer models, and display improved therapeutic potential in tumor-bearing mice. Our results demonstrate the potential of this methodology in evaluating potential caveats of viral immune evasion strategies and improving the design of oncolytic viruses. The following series of microarray experiments was utilized to assess the impact of cloning an IFN decoy receptor isolated from vaccinia virus termed B19R on the transcriptional response against an IFN sensitive maraba virus strain termed MG1. RNA extraction was performed 24h post infection in 786-0 cells. Duplicate samples were pooled, and hybridized on Affymetrix human gene 1.0 ST arrays according to manufacturer instructions. Data analysis was performed using AltAnalyze. Briefly, probeset filtering implemented a DABG threshold of 70 & pV<0.05 and utilized exclusively constitutively expressed exons to assess levels of gene expression.
2013-06-01 | E-MTAB-1636 | biostudies-arrayexpress
Project description:Previously we reported that a recombinant vaccinia virus (VACV) carrying a light-emitting fusion gene enters, replicates in, and reveals the locations of tumors in mice. A new recombinant VACV, GLV-1h68, as a simultaneous diagnostic and therapeutic agent, was constructed by inserting three expression cassettes (encoding Renilla luciferase-green fluorescent protein (RUC-GFP) fusion, b-galactosidase, and b-glucuronidase) into the F14.5L, J2R (encoding thymidine kinase, TK), and A56R (encoding hemagglutinin, HA) loci of the viral genome, respectively. Intravenous (i.v.) injections of GLV-1h68 (1 Ã 107 pfu/mouse) into nude mice with established (500 mm3) subcutaneous (s.c.) GI-101A human breast tumors were used to evaluate its toxicity, tumor targeting specificity and oncolytic efficacy. GLV-1h68 demonstrated an enhanced tumor targeting specificity and much reduced toxicity compared to its parental LIVP strains. The tumors colonized by GLV-1h68 exhibited growth, inhibition, and regression phases followed by tumor eradication within 130 days in 95% of the mice tested. Tumor regression in live animals was monitored in real time based on decreasing light emission, hence demonstrating the concept of a combined oncolytic virus-mediated tumor diagnosis and therapy system. Transcriptional profiling of regressing tumors based on a mouse-specific platform revealed gene expression signatures consistent with immune defense activation, inclusive of interferon stimulated genes (STAT-1 and IRF-7), cytokines, chemokines and innate immune effector function. These findings suggest that immune activation may combine with viral oncolysis to induce tumor eradication in this model, providing a novel perspective for the design of oncolytic viral therapies for human cancers. Objective: To determine the gene expression changes induced by GLV-1h68 vaccinia virus injection in mouse carrying human breast cancer implant and leading to tumor eradication. Methods: Gene expression was analyzed using oligonucleotide microarrays. Responsiveness to vaccina virus injection was assessed by toxicity and survival study, gene expression anaysis and tumor volume change. Result: The tumors colonized by GLV-1h68 exhibited growth, inhibition, and regression phases followed by tumor eradication within 130 days in 95% of the mice tested. Tumor regression in live animals was monitored in real time based on decreasing light emission, hence demonstrating the concept of a combined oncolytic virus-mediated tumor diagnosis and therapy system. Transcriptional profiling of regressing tumors based on a mouse-specific platform revealed gene expression signatures consistent with immune defense activation, inclusive of interferon stimulated genes (STAT-1 and IRF-7), cytokines, chemokines and innate immune effector function. Conclusion: Our findings suggest that immune activation may combine with viral oncolysis to induce tumor eradication in this model, providing a novel perspective for the design of oncolytic viral therapies for human cancers. Experiment Overall Design: tumor tissues 3 and 6 weeks post virus injection
2008-06-16 | E-GEOD-8513 | biostudies-arrayexpress
Project description:Oncolytic viruses (OV) are promising forms of immunotherapy that have demonstrated clinical benefit in difficult-to-treat cancers such as metastatic melanoma. However, their adoption in other malignancies has been limited, in part, due to poorly understood mechansims of therapeutic resistance. Here, bulk RNA-seq was performed on oncolytic vaccinia virus-sensitive and -resistant murine head and neck squamous cell carcinomas (MEERvvS and MEERvvR, respectively) to explore potential means of OV resistance. These results corroborated a potential role for TGF-beta mediated stabilization of immunosuppressive regulatory T cells in the tumor microenvironment of OV-resistant MEERvvR-bearing mice. Subsequently, treatment with oncolytic vaccinia virus engineered to expess a dominant negative TGF-β signaling inhibitor (VVtgfbi) restored sensitivity to OV-mediated cell death among MEERvvR tumors. Single-cell RNA seq performed on CD45+ immune cells isolated from tumors suggests TGF-β inhibition may also reduce the presence and activity of myeloid-derived suppressor cell populations within the tumor microenvironment.
2023-07-27 | GSE188506 | GEO
Project description:Regional delivery of oncolytic viruses has been shown to promote immune responses. Malignant pleural effusions comprise an immunosuppressive microenvironment, and the ability of oncolytic viruses to generate immune responses following regional delivery in patients with malignant pleural effusions is unknown. We conducted a phase I clinical trial that studied the intrapleural administration of oncolytic vaccinia virus to establish the safety and feasibility in patients with malignant pleural effusion due to malignant pleural mesothelioma or metastatic disease. In patients with malignant pleural mesothelioma, by correlative analysis of pre- and post-treatment tumor biopsies, we provide insight into tumor-specific viral uptake and associated immune responses.
2023-01-27 | GSE223395 | GEO
Project description:The oncolytic effect of virotherapy derives from the intrinsic capability of the applied virus in selectively infecting and killing tumor cells. Although oncolytic viruses of various constructions have been shown to efficiently infect and kill tumor cells in vitro, the efficiency of these viruses to exert the same effect on tumor cells within tumor tissues in vivo has not been extensively investigated. Here we report our studies using single-cell RNA sequencing to comprehensively analyze the gene expression profile of tumor tissues following herpes simplex virus 2-based oncolytic virotherapy. Our data revealed the extent and cell types within the tumor microenvironment that could be infected by the virus. Moreover, we observed changes in the expression of cellular genes, including antiviral genes, in response to viral infection. One notable gene found to be upregulated significantly in oncolytic virus-infected tumor cells was Gadd45g, which is desirable for optimal virus replication. These results not only help reveal the precise infection status of the oncolytic virus in vivo, but also provide insight that may lead to the development of new strategies to further enhance the therapeutic efficacy of oncolytic virotherapy.
2021-10-31 | GSE186753 | GEO
Project description:Previously we reported that a recombinant vaccinia virus (VACV) carrying a light-emitting fusion gene enters, replicates in, and reveals the locations of tumors in mice. A new recombinant VACV, GLV-1h68, as a simultaneous diagnostic and therapeutic agent, was constructed by inserting three expression cassettes (encoding Renilla luciferase-green fluorescent protein (RUC-GFP) fusion, b-galactosidase, and b-glucuronidase) into the F14.5L, J2R (encoding thymidine kinase, TK), and A56R (encoding hemagglutinin, HA) loci of the viral genome, respectively. Intravenous (i.v.) injections of GLV-1h68 (1 × 107 pfu/mouse) into nude mice with established (500 mm3) subcutaneous (s.c.) GI-101A human breast tumors were used to evaluate its toxicity, tumor targeting specificity and oncolytic efficacy. GLV-1h68 demonstrated an enhanced tumor targeting specificity and much reduced toxicity compared to its parental LIVP strains. The tumors colonized by GLV-1h68 exhibited growth, inhibition, and regression phases followed by tumor eradication within 130 days in 95% of the mice tested. Tumor regression in live animals was monitored in real time based on decreasing light emission, hence demonstrating the concept of a combined oncolytic virus-mediated tumor diagnosis and therapy system. Transcriptional profiling of regressing tumors based on a mouse-specific platform revealed gene expression signatures consistent with immune defense activation, inclusive of interferon stimulated genes (STAT-1 and IRF-7), cytokines, chemokines and innate immune effector function. These findings suggest that immune activation may combine with viral oncolysis to induce tumor eradication in this model, providing a novel perspective for the design of oncolytic viral therapies for human cancers. Objective: To determine the gene expression changes induced by GLV-1h68 vaccinia virus injection in mouse carrying human breast cancer implant and leading to tumor eradication. Methods: Gene expression was analyzed using oligonucleotide microarrays. Responsiveness to vaccina virus injection was assessed by toxicity and survival study, gene expression anaysis and tumor volume change. Result: The tumors colonized by GLV-1h68 exhibited growth, inhibition, and regression phases followed by tumor eradication within 130 days in 95% of the mice tested. Tumor regression in live animals was monitored in real time based on decreasing light emission, hence demonstrating the concept of a combined oncolytic virus-mediated tumor diagnosis and therapy system. Transcriptional profiling of regressing tumors based on a mouse-specific platform revealed gene expression signatures consistent with immune defense activation, inclusive of interferon stimulated genes (STAT-1 and IRF-7), cytokines, chemokines and innate immune effector function. Conclusion: Our findings suggest that immune activation may combine with viral oncolysis to induce tumor eradication in this model, providing a novel perspective for the design of oncolytic viral therapies for human cancers. Keywords: Responsiveness to vaccina virus injection
2007-12-26 | GSE8513 | GEO
Project description:Background:
* Immune-based approaches in colorectal cancer have unfortunately with the notable exception of immune checkpoint inhibition in microsatellite instable (MSI-hi) disease been largely unsuccessful. The reasons for this are unclear but no doubt relate to the fact that in advanced disease colorectal cancer appears to be less immunogenic, as evidenced by the lack of infiltrating lymphocytes with advancing T stage
* Pexa-Vec (JX-594) is a thymidine kinase gene-inactivated oncolytic vaccinia virus engineered for the expression of transgenes encoding human granulocyte- macrophage colony-stimulating factor (GM-CSF) and beta-galactosidase. Apart from the direct oncolytic activity, oncolytic viruses such as Pexa-Vec have been shown to mediate tumor cell death via the induction of innate and adaptive immune responses
* Tremelimumab is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expressed on the surface of activated T lymphocytes and causes inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Durvalumab is a human monoclonal antibody directed against programmed death-ligand 1 (PD-L1).
* The aim of the study is to evaluate whether the anti-tumor immunity induced by Pexa-Vec oncolytic viral therapy can be enhanced by immune checkpoint inhibition.
Objective:
-To determine the safety, tolerability and feasibility of Pexa-Vec oncolytic virus in combination with immune checkpoint inhibition in patients with refractory metastatic colorectal cancer.
Eligibility:
* Histologically confirmed metastatic colorectal cancer.
* Patients must have progressed on, been intolerant of or refused prior oxaliplatin- and irinotecan-containing, fluorouracil-based, chemotherapeutic regimen and have disease that is not amenable to potentially curative resection. Patients who have a known Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type tumor must have progressed, been intolerant of or refused cetuximab or panitumumab based chemotherapy.
* Patients tumors must be documented to be microsatellite-stable (MSS) either by genetic analysis or immunohistochemistry OR microsatellite-high with documented disease progression following anti-programmed cell death protein 1 (PD1)/Programmed death-ligand 1 (PDL1) therapy.
* Patients must have at least one focus of metastatic disease that is amenable to pre- and on-treatment biopsy.
* Willingness to undergo mandatory tumor biopsy.
Design:
-The proposed study is Phase I/II study of Pexa-Vec oncolytic virus at two dose levels in combination with immune checkpoint inhibition in patients with metastatic colorectal cancer.
| 2248442 | ecrin-mdr-crc
Project description:Our experiments have demonstrated that VEGF signalling is a critical component of oncolytic virus infection in tumor vasculature. This effect is in part mitigated by downstream activation of the master immunoloigcal transcriptional repressor known as PRD/BF1. To investigate the role of the VEGF-PRD/BF1 signalling axis in the context of oncolytic virus infection, we isolated the RNA from sub-confluent human umbilical vein endothelial cells treated under four conditions (siRNA Control, siRNA Control + WyTK-, siRNA Control + WyTK- + VEGF165 and siRNA PRD/BF1 + WyTK- + VEGF165. Using the RNA pooled from four experiments, the goal of this study was to determine the nature & fraction of genes repressed by VEGF in the context of infection, which could be rescued by PRD/BF1.
2015-07-10 | E-MTAB-2963 | biostudies-arrayexpress