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Engineering a novel HSV-1 strain for oncolytic therapy of solid tumors

ABSTRACT: Oncolytic HSV-1 derived viruses are being developed for cancer treatment. Here we describe the isolation of a novel strain of HSV-1, and its engineering to safely harness it as an oncolytic therapeutic. This strain (UT1a) was isolated from a de-identified consented patient biorepository. CRISPR-Cas9-based recombination was utilized to insert bacterial artificial chromosome (BAC) genes into the viral UL39 and UL40 locus resulting in the deletion of both large and small subunits of the viral ribonucleotide reductase (RR). Subsequent deletion of viral RL1 genes encoding the neurovirulence factor ɣ34.5, resulted in OncoDelta (OncoD), a virus deleted for UL39, UL40 and both copies of RL1. OncoD retained tumor cell specific cytotoxicity and replication, was safe and non-toxic in intracranial injections in naïve mice up to doses of (5 x 106), maximal injectable dose OncoD and showed significant anti-tumor immune activating potential in multiple tumor models. Transcriptome profiling of OncoD showed that it impaired DNA damage repair pathways and hence synergized with radiation to improve therapeutic response in vitro and in vivo.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288846 | GEO | 2025/04/09

REPOSITORIES: GEO

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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

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Engineering a novel HSV-1 strain for oncolytic therapy of solid tumors

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