Development of gene therapeutics using oncolytic adenovirus to disrupt EBV latency in cancer
Oncolytic viruses selectively target tumors while stimulating antitumor immunity. We developed Ad-TBZ, an oncolytic adenovirus driven by the hTERT promoter and engineered to express the EBV lytic activator BZLF1, specifically targeting EBV-associated gastric cancer (EBVaGC), which accounts for ~10% of global gastric cancers. Ad-TBZ was constructed by inserting an hTERTp-controlled E1A/IRES-E1B cassette upstream of the CMV promoter-driven BZLF1 gene, enabling selective replication in EBVaGC cells while sparing normal fibroblasts. Compared to a control virus lacking BZLF1 (Ad-T-pA), Ad-TBZ exhibited enhanced cytotoxicity in AGS-EBV and SNU719 cells. Ad-TBZ triggered EBV lytic reactivation by upregulating key viral genes and increasing EBV genome copies, leading to significant late apoptosis (10–80%). In xenograft models, Ad-TBZ suppressed tumor growth without affecting body weight. While combination therapies with oxaliplatin, cisplatin, or ganciclovir provided limited benefit, Ad-TBZ alone showed strong anticancer efficacy via virus-mediated oncolysis and EBV reactivation-induced apoptosis. These findings highlight Ad-TBZ as a promising standalone therapy, potentially reducing the need for chemotherapy in EBVaGC.
2025 Spring Convention