Dataset Information

Generation of a Tumor-Specific Chemokine Gradient Using Oncolytic Vesicular Stomatitis Virus Encoding CXCL9.

ABSTRACT: Genetically modified vesicular stomatitis virus (VSV) is an attractive agent for cancer treatment due to rapid intratumoral replication and observed clinical responses. Although VSV selectively kills malignant cells and can boost antitumor immunity, limited induction of intratumoral immune infiltration remains a barrier to efficacy in some cancer models. Here we engineered the oncolytic VSV platform to encode the T cell chemokine CXCL9, which is known to mediate the recruitment of activated CD8+ cytotoxic T cells and CD4+ T helper cells, and demonstrates conserved protein function between mice and humans. Chemotactic activity of the virally encoded chemokine was confirmed in vitro. Intratumoral concentration of CXCL9 was shown to increase after VSV therapy in three different cancer models, but to a much greater degree after VSV-CXCL9 therapy as compared with VSV control viruses. Despite a steep chemokine gradient from the tumor to the bloodstream, tumor trafficking of adoptively transferred and endogenous T cells was not measurably increased following VSV-CXCL9 therapy. Our results indicate that oncolytic VSV infection promotes release of CXCL9 in the tumor microenvironment, but further boosting of the functional chemokine gradient through virus engineering has little incremental impact on intratumoral immune cell infiltration in mouse and human tumor models.

SUBMITTER: Eckert EC

PROVIDER: S-EPMC6951834 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Generation of a Tumor-Specific Chemokine Gradient Using Oncolytic Vesicular Stomatitis Virus Encoding CXCL9.

Eckert Elizabeth C EC Nace Rebecca A RA Tonne Jason M JM Evgin Laura L Vile Richard G RG Russell Stephen J SJ

Molecular therapy oncolytics 20191214

Genetically modified vesicular stomatitis virus (VSV) is an attractive agent for cancer treatment due to rapid intratumoral replication and observed clinical responses. Although VSV selectively kills malignant cells and can boost antitumor immunity, limited induction of intratumoral immune infiltration remains a barrier to efficacy in some cancer models. Here we engineered the oncolytic VSV platform to encode the T cell chemokine CXCL9, which is known to mediate the recruitment of activated CD8< ...[more]

PMID: 31930167

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Project description:BackgroundM protein mutant vesicular stomatitis virus (M51R-VSV) has oncolytic properties against many cancers. However, some cancer cells are resistant to M51R-VSV. Herein, we evaluate the molecular determinants of vesicular stomatitis virus (VSV) resistance in pancreatic adenocarcinoma cells.MethodsCell viability and the effect of β-interferon (IFN) were analyzed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. Gene expression was evaluated via microarray analysis. Cell infectability was measured by flow cytometry. Xenografts were established in athymic nude mice and treated with intratumoral M51R-VSV.ResultsFour of five pancreatic cancer cell lines were sensitive to M51R-VSV, whereas Panc 03.27 cells remained resistant (81 ± 3% viability 72 h after single-cycle infection). Comparing sensitive MiaPaCa2 cells with resistant Panc 03.27 cells, significant differences in gene expression were found relating to IFN signaling (P = 2 × 10(-5)), viral entry (P = 3 × 10(-4)), and endocytosis (P = 7 × 10(-4)). MiaPaCa2 cells permitted high levels of VSV infection, whereas Panc 03.27 cells were capable of resisting VSV cell entry even at high multiplicities of infection. Extrinsic β-IFN overcame apparent defects in IFN-mediated pathways in MiaPaCa2 cells conferring VSV resistance. In contrast, β-IFN decreased cell viability in Panc 3.27 cells, suggesting intact antiviral mechanisms. VSV-treated xenografts exhibited reduced tumor growth relative to controls in both MiaPaCa2 (1423 ± 345% versus 164 ± 136%; P < 0.001) and Panc 3.27 (979 ± 153% versus 50 ± 56%; P = 0.002) tumors. Significant lymphocytic infiltration was seen in M51R-VSV-treated Panc 03.27 xenografts.ConclusionsInhibition of VSV endocytosis and intact IFN-mediated defenses are responsible for M51R-VSV resistance in pancreatic adenocarcinoma cells. M51R-VSV treatment appears to induce antitumor cellular immunity in vivo, which may expand its clinical efficacy.

Project description:BackgroundImmunotherapies, driven by immune-mediated antitumorigenicity, offer the potential for significant improvements to the treatment of multiple cancer types. Identifying therapeutic strategies that bolster antitumor immunity while limiting immune suppression is critical to selecting treatment combinations and schedules that offer durable therapeutic benefits. Combination oncolytic virus (OV) therapy, wherein complementary OVs are administered in succession, offer such promise, yet their translation from preclinical studies to clinical implementation is a major challenge. Overcoming this obstacle requires answering fundamental questions about how to effectively design and tailor schedules to provide the most benefit to patients.MethodsWe developed a computational biology model of combined oncolytic vaccinia (an enhancer virus) and vesicular stomatitis virus (VSV) calibrated to and validated against multiple data sources. We then optimized protocols in a cohort of heterogeneous virtual individuals by leveraging this model and our previously established in silico clinical trial platform.ResultsEnhancer multiplicity was shown to have little to no impact on the average response to therapy. However, the duration of the VSV injection lag was found to be determinant for survival outcomes. Importantly, through treatment individualization, we found that optimal combination schedules are closely linked to tumor aggressivity. We predicted that patients with aggressively growing tumors required a single enhancer followed by a VSV injection 1 day later, whereas a small subset of patients with the slowest growing tumors needed multiple enhancers followed by a longer VSV delay of 15 days, suggesting that intrinsic tumor growth rates could inform the segregation of patients into clinical trials and ultimately determine patient survival. These results were validated in entirely new cohorts of virtual individuals with aggressive or non-aggressive subtypes.ConclusionsBased on our results, improved therapeutic schedules for combinations with enhancer OVs can be studied and implemented. Our results further underline the impact of interdisciplinary approaches to preclinical planning and the importance of computational approaches to drug discovery and development.

Dataset Information

Generation of a Tumor-Specific Chemokine Gradient Using Oncolytic Vesicular Stomatitis Virus Encoding CXCL9.

Publications

Generation of a Tumor-Specific Chemokine Gradient Using Oncolytic Vesicular Stomatitis Virus Encoding CXCL9.

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