作者: Ikeda, Minako ; Mitsui, Kaoru ; Matsuda, Eriko ; Kamisasanuki, Taro ; Nagano, Satoshi ; Horikawa, Yoshiharu ; Kamizono, Junichi ; Nishikawaji, Yuya ; Kosai, Ken-Ichiro ; Kosai, Ken-ichiro

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.

2019-12-01·BMC Cancer2区 · 医学

A survivin-responsive, conditionally replicating adenovirus induces potent cytocidal effects in adult T-cell leukemia/lymphoma

2区 · 医学

ArticleOA

作者: Suzuki, Shinsuke ; Kosai, Ken-Ichiro ; Arima, Naomichi ; Ishitsuka, Kenji ; Ueno, Shin-Ichi ; Kofune, Hiroki ; Uozumi, Kimiharu ; Yoshimitsu, Makoto

BACKGROUNDAdult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by long-term human T-cell leukemia virus type I (HTLV-1) infection. Survivin-responsive, conditionally replicating adenoviruses regulated by multiple tumor-specific factors (Surv.m-CRAs), in which the expression of the adenoviral early region 1A gene is regulated by the survivin (BIRC5) promoter, can be used to treat several cancers. As survivin is overexpressed in ATL, we examined the effects of Surv.m-CRAs on ATL-selective replication and survival.METHODSWe tested two ATL cell lines and four HTLV-1-infected T-cell lines. The cells were subjected to infection with either E1-deleted, replication-defective adenoviruses or Surv.m-CRAs at various multiplicities of infection.RESULTSStrong activation of survivin promoter was observed in all six cell lines. Moreover, the expression of the coxsackie and adenovirus receptor (CAR), which is important for adenoviral infection, was high in the cell lines. In contrast, we observed the absence of survivin promoter activity and a low expression of CAR in activated peripheral blood lymphocytes (PBLs) from healthy subjects. Surv.m-CRAs actively replicated and induced cytocidal effects in five out of six cell lines; conversely, we observed minimal viral replication and no marked cytotoxicity in normal activated PBLs.CONCLUSIONSThis is the first report demonstrating that Surv.m-CRAs constitute attractive potential anti-ATL agents.

2019-03-01·Japanese Journal of Clinical Oncology4区 · 医学

Oncolytic virus therapy in Japan: progress in clinical trials and future perspectives

4区 · 医学

Review

作者: Taguchi, Satoru ; Fukuhara, Hiroshi ; Todo, Tomoki

Oncolytic virus therapy is a promising new option for cancer. It utilizes genetically engineered or naturally occurring viruses that selectively replicate in and kill cancer cells without harming normal cells. T-VEC (talimogene laherparepvec), a second-generation oncolytic herpes simplex virus type 1, was approved by the US Food and Drug Administration for the treatment of inoperable melanoma in 2015 and subsequently approved in Europe in 2016. Other oncolytic viruses using different parental viruses have also been tested in Phase III clinical trials and are ready for drug approval: Pexa-Vec (pexastimogene devacirepvec), an oncolytic vaccinia virus, CG0070, an oncolytic adenovirus, and REOLYSIN (pelareorep), an oncolytic reovirus. In Japan, as of May 2018, several oncolytic viruses have been developed, and some have already proceeded to clinical trials. In this review, we summarize clinical trials assessing oncolytic virus therapy that were conducted or are currently ongoing in Japan, specifically, T-VEC, the abovementioned oncolytic herpes simplex virus type 1, G47Δ, a third-generation oncolytic herpes simplex virus type 1, HF10, a naturally attenuated oncolytic herpes simplex virus type 1, Telomelysin, an oncolytic adenovirus, Surv.m-CRA, another oncolytic adenovirus, and Sendai virus particle. In the near future, oncolytic virus therapy may become an important and major treatment option for cancer in Japan.

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