Kagoshima University · Graduate School of Medical and Dental Sciences

Research keywordsconditionally replicating adenovirus・oncolytic virotherapy・gene therapy・cytokine transgene expression・tumor-selective promoters・cancer drug delivery

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• Kamizono J., Nishikawaji Y., Nagano S., Ikeda M., Horikawa Y., Kamisasanuki T., Mitsui K., Matsuda E., Kosai K.i. . Triple-regulated conditionally replicating adenovirus for effective and safe2024 · 記述言語： 日本語 出版者・発行元： Biochemical and Biophysical Research Communications There is no effective therapy for peritoneal carcinomatosis derived from gastric cancer. An ideal conditionally replicating adenovirus (CRA) that selectively replicates in and kills cancer cells has not been developed for gastric cancer-derived peritoneal carcinomatosis. Using our platform technology of CRA regulated and treating tumors with multiple factors (m-CRA), we generated two types of survivin-responsive m-CRAs, Surv.m-CRA-CMVp and Surv.m-CRA-CEAp, consisting of E1A downstream of the survivin promoter, and the mutated E1B gene downstream of the human cytomegalovirus immediate early gene enhancer/promoter and carcinoembryonic antigen promoter, respectively. Survivin mRNA was expressed at high and undetectable levels in two gastric cancer cells and eleven normal cells, respectively. Carcinoembryonic antigen was expressed at high and very low levels in MKN-45 gastric cancer and normal PrEC cells, respectively, and was not detected in other cell types. While both Surv.m-CRA-CEAp and Surv.m-CRA-CMVp exhibited potent cytotoxic effects on MKN-45 cells in vitro, Surv.m-CRA-CEAp significantly reduced cytotoxicity to normal cells compared to Surv.m-CRA-CMVp. Control mice that received an intraperitoneal injection of MKN-45 cells gradually lost body weight and died of peritoneal carcinomatosis within 98 days. In contrast, all mice receiving Surv.m-CRA-CEAp or Surv.m-CRA-CMVp-infected MKN-45 cells increased their body weight and survived 120 days. In conclusion, the triple-regulated Surv.m-CRA-CEAp enhances cancer specificity (i.e., safety) without reducing the potent therapeutic effect for carcinoembryonic antigen-positive gastric cancer-derived peritoneal carcinomatosis. The modified E1B promoter strategy of CRA facilitates the development of novel CRAs for the effective and safe treatment of a variety of refractory cancers. DOI： 10.1016/j.bbrc.2024.150894 Scopus PubMed
• Kawakami H., Ijichi N., Obama Y., Matsuda E., Mitsui K., Nishikawaji Y., Watanabe M., Nagano S., Taniguchi N., Komiya S., Kosai K.i. . An optimal promoter regulating cytokine transgene express2024 · 記述言語： 日本語 出版者・発行元： Translational Research 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. DOI： 10.1016/j.trsl.2024.07.002 Scopus PubMed
• 小戝 健一郎, 西川路 侑耶, 伊集院 広壮, 松田 恵理子, 三井 薫 . 多因子増殖制御型アデノウイルスによる画期的ながん治療 . Ｄｒｕｇ Ｄｅｌｉｖｅｒｙ Ｓｙｓｔｅｍ39 ( 4 ) 248 - 259 2024年9月 詳細を見る 記述言2024 · 記述言語： 日本語 出版者・発行元： 日本DDS学会 非増殖型アデノウイルス（Ad）ベクターが1990年代の<i>in vivo</i>がん遺伝子治療の研究を牽引し、2000年代より腫瘍溶解性ウイルス（OV）の制限増殖型Ad（CRA）の開発が本格化し、近年は免疫遺伝子搭載型CRAの研究と臨床応用が盛んである。筆者らは、複雑に遺伝子改変したCRA（多因子増殖制御型CRA；m-CRA）を多種多様・効率的に作製できるプラットフォーム技術を開発し、サバイビン反応性m-CRA（Surv.m-CRA）を創出した。治療遺伝子未搭載のSurv.m-CRA-1は、治療抵抗性の悪性骨腫瘍への早期承認を目指した多施設共同・第Ⅱ相医師主導治験を現在進めている。さらに最近、安全かつ最大の治療効果を得るための、免疫遺伝子搭載OVにおける「至適プロモーターによる至適発現の必要性」という新概念を見出した。本稿ではAdのウイルス学に続いて上記を概説し、次世代CRAの展望について述べる。 DOI： 10.2745/dds.39.248 Scopus CiNii Research
• Watanabe M., Nishikawaji Y., Kawakami H., Kosai K.I. . Adenovirus biology, recombinant adenovirus, and adenovirus usage in gene therapy . Viruses13 ( 12 )記述言語： 日本語 出版者・発行元： Viruses Gene therapy is currently in the public spotlight. Several gene therapy products, including oncolytic virus (OV), which predominantly replicates in and kills cancer cells, and COVID-19 vaccines have recently been commercialized. Recombinant adenoviruses, including replication-defective adenoviral vector and conditionally replicating adenovirus (CRA; oncolytic adenovirus), have been extensively studied and used in clinical trials for cancer and vaccines. Here, we review the biology of wild-type adenoviruses, the methodological principle for constructing recombinant adenoviruses, therapeutic applications of recombinant adenoviruses, and new technologies in pluripotent stem cell (PSC)-based regenerative medicine. Moreover, this article describes the technology platform for efficient construction of diverse “CRAs that can specifically target tumors with multiple factors” (m-CRAs). This technology allows for modification of four parts in the adenoviral E1 region and the subsequent insertion of a therapeutic gene and promoter to enhance cancer-specific viral replication (i.e., safety) as well as therapeutic effects. The screening study using the m-CRA technology successfully identified survivin-responsive m-CRA (Surv.m-CRA) as among the best m-CRAs, and clinical trials of Surv.m-CRA are underway for patients with cancer. This article also describes new recombinant adenovirus-based technologies for solving issues in PSC-based regenerative medicine. DOI： 10.3390/v13122502 Scopus PubMed

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