An optimal promoter regulating cytokine transgene expression is crucial for safe and effective oncolytic virus immunotherapy

• Published in: Translational research : the journal of laboratory and clinical medicine Vol. 273; pp. 32 - 45
• Main Authors: Kawakami, Hirotaka, Ijichi, Nobuhiro, Obama, Yuki, Matsuda, Eriko, Mitsui, Kaoru, Nishikawaji, Yuya, Watanabe, Maki, Nagano, Satoshi, Taniguchi, Noboru, Komiya, Setsuro, Kosai, Ken-ichiro
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2024
• Subjects: Animals; Cancer immunotherapy; Cell Line, Tumor; Conditionally replicating adenovirus targeting and/or treating tumors with multiple factors (m-CRAs); Conditionally-replicating adenovirus (CRA); Cricetinae; Cytokine; Cytokines - metabolism; E2F; Granulocyte macrophage colony-stimulating factor (GM-CSF); Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Humans; Immunotherapy - methods; Mesocricetus; Oncolytic Virotherapy - methods; Oncolytic virus; Oncolytic Viruses - genetics; Promoter activity; Promoter Regions, Genetic; Safety; Survivin; Transgenes; Conditionally-replicating adenovirus (CRA); OVI; AGTE; GLP; Cancer immunotherapy; EGFP; GM-CSF; E2F; SHCL; Safety; mGM-CSF; CA; E1B∆55K; OS; MOI; Cytokine; OV; IL-2; Oncolytic virus; Survivin; CMV; Promoter activity; Granulocyte macrophage colony-stimulating factor (GM-CSF); CRA; NEAA; RSV; Conditionally replicating adenovirus targeting and/or treating tumors with multiple factors (m-CRAs); Surv.m-CRAs; m-CRAs; hTERT; pfu
• ISSN: 1931-5244; 1878-1810; 1878-1810
• DOI: 10.1016/j.trsl.2024.07.002

In general, ensuring safety is the top priority of a new modality. Although oncolytic virus armed with an immune stimulatory transgene (OVI) showed some promise, the strategic concept of simultaneously achieving maximum effectiveness and minimizing side effects has not been fully explored. We generated a variety of survivin-responsive “conditionally replicating adenoviruses that can target and treat cancer cells with multiple factors (m-CRAs)” (Surv.m-CRAs) armed with the granulocyte-macrophage colony-stimulating factor (GM-CSF) transgene downstream of various promoters using our m-CRA platform technology. We carefully analyzed both therapeutic and adverse effects of them in the in vivo syngeneic Syrian hamster cancer models. Surprisingly, an intratumor injection of a conventional OVI, which expresses the GM-CSF gene under the constitutively and strongly active “cytomegalovirus enhancer and β-actin promoter”, provoked systemic and lethal GM-CSF circulation and shortened overall survival (OS). In contrast, a new conceptual type of OVI, which expressed GM-CSF under the cancer-predominant and mildly active E2F promoter or the moderately active “Rous sarcoma virus long terminal repeat”, not only abolished lethal adverse events but also prolonged OS and systemic anti-cancer immunity. Our study revealed a novel concept that optimal expression levels of an immune stimulatory transgene regulated by a suitable upstream promoter is crucial for achieving high safety and maximal therapeutic effects simultaneously in OVI therapy. These results pave the way for successful development of the next-generation OVI and alert researchers about possible problems with ongoing clinical trials.