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An optimal promoter regulating cytokine transgene expression is crucial for safe and effective oncolytic virus immunotherapy.
Kawakami, Hirotaka; Ijichi, Nobuhiro; Obama, Yuki; Matsuda, Eriko; Mitsui, Kaoru; Nishikawaji, Yuya; Watanabe, Maki; Nagano, Satoshi; Taniguchi, Noboru; Komiya, Setsuro; Kosai, Ken-Ichiro.
Affiliation
  • Kawakami H; Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; Department of Orthopaedic Surgery, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
  • Ijichi N; Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
  • Obama Y; Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
  • Matsuda E; Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
  • Mitsui K; Center for Innovative Therapy Research and Application, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
  • Nishikawaji Y; Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
  • Watanabe M; Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
  • Nagano S; Department of Orthopaedic Surgery, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; Center for Innovative Therapy Research and Application, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; Department of Clinical P
  • Taniguchi N; Department of Orthopaedic Surgery, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; Center for Innovative Therapy Research and Application, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
  • Komiya S; Department of Orthopaedic Surgery, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; Center for Innovative Therapy Research and Application, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
  • Kosai KI; Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; Center for Innovative Therapy Research and Application, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-
Transl Res ; 273: 32-45, 2024 Nov.
Article in En | MEDLINE | ID: mdl-38969167
ABSTRACT
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 ß-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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Granulocyte-Macrophage Colony-Stimulating Factor / Promoter Regions, Genetic / Transgenes / Oncolytic Viruses / Oncolytic Virotherapy / Immunotherapy Limits: Animals / Humans Language: En Journal: Transl Res Journal subject: MEDICINA / TECNICAS E PROCEDIMENTOS DE LABORATORIO Year: 2024 Document type: Article Affiliation country: Japan Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Granulocyte-Macrophage Colony-Stimulating Factor / Promoter Regions, Genetic / Transgenes / Oncolytic Viruses / Oncolytic Virotherapy / Immunotherapy Limits: Animals / Humans Language: En Journal: Transl Res Journal subject: MEDICINA / TECNICAS E PROCEDIMENTOS DE LABORATORIO Year: 2024 Document type: Article Affiliation country: Japan Country of publication: United States