Tumor-targeting oncolytic viruses engineered for glioblastoma immunotherapy
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ABSTRACT:
PROVIDER: PRJNA1021139 | ENA |
REPOSITORIES: ENA
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Project description:We report the development of an oncolytic virus engineered for enhanced targeting of tumor cells, increased safety, and greater antitumor efficacy through the expression of multiple transgenes that remodel the immunosuppressive GBM tumor microenvironment
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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.
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Project description:Oncolytic biomineralized bacteria for tumor immunotherapy
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Project description:We explored the utility of oncolytic virus therapy against glioblastoma with Zika virus (ZIKV), a flavivirus that induces cell death and differentiation of neural precursor cells in the developing fetus. ZIKV preferentially infected and killed glioblastoma stem cells (GSCs) relative to differentiated tumor progeny or normal neuronal cells. The effects against GSCs were not a general property of neurotropic flaviviruses, as West Nile Virus (WNV) indiscriminately killed both tumor and normal neural cells. ZIKV potently depleted patient-derived GSCs grown in culture and in organoids. Moreover, mice with glioblastoma survived substantially longer and at greater rates when the tumor was inoculated with a murine adapted strain of ZIKV. Our results suggest that ZIKV is an oncolytic virus that can preferentially target GSCs, and thus, genetically modified strains that further optimize safety could have therapeutic efficacy for adult glioblastoma patients.
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Project description:Autophagy-overactivated composite microbe engineered from oncolytic adenoviruses for the cascade enhancement of cancer immunotherapy
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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:In this study we demonstrate the effect of oncolytic adenoviruses armed with CXCL9, CXCL10 and IL-15 to infect cancer cells, secrete the encoded protein and drive gradient-dependent T-cell attraction. Our in vivo validation demonstrated an increased intratumoral CD4+ and CD8+ T-cell infiltration following treatment with armed viruses compared to control groups. Finally, RCC cells were screened for tumor-specific peptides to validate their immunogenicity in a (personalized) oncolytic cancer vaccine approach, previously referred to as PeptiCRAd.
2025-05-06 | PXD051880 | Pride
Project description:An acquisition of increased sensitivity of cancer cells to viruses is a common outcome of malignant progression that justifies the development of oncolytic viruses as anticancer therapeutics. Studying molecular changes that underlie the sensitivity to viruses would help to identify cases where oncolytic virus therapy would be most effective. We quantified changes in protein abundances in glioblastoma multiforme (GBM) and osteosarcoma cell lines that differ in the ability to induce resistance to vesicular stomatitis virus (VSV) infection in response to type I interferon (IFN) treatment. In IFN-treated samples we observed an up-regulation of protein products of some IFN-regulated genes (IRGs). In total, the proteome analysis revealed up to 20% more proteins encoded by IRGs in the glioblastoma cell line, which develops resistance to VSV infection after pre-treatment with IFN. In both cell lines protein-protein interaction and signaling pathway analyses have revealed a significant stimulation of processes related to type I IFN signaling and defense responses to viruses. The study has shown that the up-regulation of IRG proteins induced by the IFNα treatment of GBM cells can be detected at the proteome level. Similar analyses could be applied for revealing functional alterations within the antiviral mechanisms in glioblastoma samples, accompanying by acquisition of sensitivity to oncolytic viruses.
2022-06-09 | PXD022868 | Pride
Project description:Oncolytic viruses (OV) kill tumour cells directly and induce anti-tumour immunity. We analysed gene expression profiles in human NK cells following treatment of PBMC with oncolytic reovirus in vitro.
2022-01-03 | E-MTAB-9826 | biostudies-arrayexpress
Project description:To further develop gene expression approach, we have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to identify oncolytic virus (OV) infection effect in different subpopulations of glioblastoma stem-like cells (G cells). Cells were transfected with either control or OV. OV affects gene expression patterns in cell subtype specific pattern.
2020-07-29 | GSE155247 | GEO