Telomerase-specific virotherapy in an animal model of human head and neck cancer

Nakajima, Oumi; Matsunaga, Atsuko; Ichimaru, Daiju; Urata, Yasuo; Fujiwara, Toshiyoshi; Kawakami, Koji

doi:10.1158/1535-7163.mct-08-0620

Cited by 10 publications

(5 citation statements)

References 27 publications

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“…injections of OBP-301 dramatically inhibited the growth of KCCT873 tumors in vivo (15). The present study adds to the antitumor profile of OBP-301 in SCCHN tumor-bearing mice, showing that OBP-301 has antitumor activity against large tumors.…”

Section: Discussionsupporting

confidence: 54%

“…We have previously reported that a 5-day i.t. administration of OBP-301 to nude mice bearing subcutaneous KCCT873 human SCCHN xenografts had significant antitumor activity (15). In the present study, we extend this work by assessing the antitumor activity of OBP-301 in advanced SCCHN tumors.…”

Section: Introductionmentioning

confidence: 56%

“…To achieve this tumor specificity, OBP-301 was developed from a replicationselective tumor-specific oncolytic adenovirus. OBP-301 has been shown to be effective against human cancers (8,9,15). A phase I study has been initiated in the US to assess the safety and tolerability of OBP-301 in patients with various types of progressive solid cancers, including SCCHN.…”

Section: Discussionmentioning

confidence: 99%

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Use of telomelysin (OBP-301) in mouse xenografts of human head and neck cancer

et al. 2009

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Abstract. We previously reported that telomerase-specific replication-component adenovirous, Telomelysin has cytotoxic activity to the YCUT892, KCCT873, KCCT891, KCCL871, YCUM862, HN12, and KCCOR891 cell lines in vitro, and investigated the association between cytotoxic activity and adenoviral receptor expression. In this study, we evaluated the most appropriate way to administer telomelysin (OBP-301) in the treatment of squamous cell carcinoma of the head and neck (SCCHN), and assessed the effect of OBP-301 in large subcutaneous KCCT873 human SCCHN tumors in immunodeficient mice. We also compared antitumor responses following three intratumoral (i.t.) injections of OBP-301 given daily, every 2 days or weekly. To investigate the mechanism of the antitumor effect, we evaluated cellular infiltration in treated tumors. OBP-301 showed remarkable antitumor activity against large KCCT873 tumors, and three treatment schedules produced similar antitumor effects. The weekly regimen also significantly reduced the growth of large tumors. Immunochemistry revealed that macrophages, but not natural killer cells, were responsible for tumor regression. A regimen of three weekly injections of OBP-301 has remarkable antitumor effects against large KCCT873 tumors. These results may provide a new platform for treating patients with localized SCCHN. IntroductionSquamous cell carcinoma of the head and neck (SCCHN) accounts for 5% of newly diagnosed cancers in adults in the US and 8% of cancers worldwide (1). Most patients are treated with various combinations of surgery, radiotherapy and systemic agents, but treatment fails in about half of patients (2). In light of the poor outlook for patients with recurrent disease, additional effective local-regional therapies are clearly required for the treatment of SCCHN. Conditionally replicating viruses targeted to tumors are being developed as a novel class of oncolytic agents. Oncolytic virotherapy has been evaluated in clinical trials of patients with SCCHN. For example, in a phase II trial, the addition of systemic cisplatin or 5-fluorouracil following direct intratumoral (i. t.) injection of the oncolytic adenovirus ONXY-015 resulted in clinical regression of SCCHN tumors (3).Telomerase is a ribonucleoprotein complex responsible for the complete replication of chromosomal ends (4). It is expressed in >85% of human cancers (5) but in only a few normal somatic cells (6). Telomerase activation is considered to be a critical step in carcinogenesis, and its activity is closely correlated to expression of human telomerase reverse transcriptase (hTERT) (7). hTERT can therefore be exploited as a cancer-specific promoter.Telomelysin (OBP-301) is a telomerase-specific replicationcompetent adenovirus vector in which the hTERT promoter element drives the expression of E1A and E1B genes, which are linked to an internal ribosome entry site (8,9). Telomelysin has been shown to selectively kill human cancer cells (8-11). In infected human tumor cells in vitro, OBP-301 replication produces the endogeno...

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Section: Discussionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

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Use of telomelysin (OBP-301) in mouse xenografts of human head and neck cancer

et al. 2009

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“…As E1A expression correlates directly with overall virus efficacy, the ability of the host cell to permit expression would profoundly influence all subsequent parts of the life cycle. However, previous studies found that E1A expression does not correspond with CAR and hTERT expression; hence, the levels of expression vary widely and do not correlate with OBP-301 sensitivity (12,27). Furthermore, a recent report showed that OBP-702, in which a human wild-type p53 gene expression cassette was inserted into the E3 region of OBP-301 suppressed the viability of cancer cells more efficiently than OBP-301, inducing dual apoptotic and autophagic cell death (28,29).…”

Section: Discussionmentioning

confidence: 99%

Antitumor effects of telomerase-specific replication-selective oncolytic viruses for adenoid cystic carcinoma cell lines

et al. 2013

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We evaluated the antitumor effect of a telomerase-specific replication-selective adenovirus (Telomelysin, OBP-301) for adenoid cystic carcinoma (ACC) in vitro and in vivo. Adenovirus E1 gene expression was controlled by human telomerase reverse transcription (hTERT). Infection of ACC cells by OBP-301 induced high E1A mRNA expression and subsequent oncolytic cell death in a dose-dependent manner. Using OBP-401 (TelomeScan), a genetically engineered adenovirus that carries the GFP gene under the control of the cytomegalovirus (CMV) promoter at the deleted E3 region of OBP-301, ACC cells expressed bright GFP fluorescence as early as 12 h after OBP-401 infection. The fluorescence intensity gradually increased in a time-dependent manner, followed by rapid cell death due to the cytopathic effect of OBP-401, as evidenced by the floating, highly light-refractive cells using phase-contrast microscopy. Effects of intratumorally injected OBP-401 against established Acc2 xenograft tumors were seen in BALB/c nu/nu mice. The levels of GFP expression following ex vivo infection of OBP-401 may be of value as a positive predictive marker for the outcome of telomerase-specific virotherapy. Our data clearly indicated that telomerase-specific oncolytic adenoviruses have significant therapeutic potential against human ACC in vitro and in vivo. These results suggest that treatment with OBP-301 and OBP-401 may improve the quality of life of oral cancer patients.

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“… 73 OBP-301 induces tumor-selective oncolysis and antitumor effect in a telomerase-dependent manner in various cancer cells; eg, head and neck cancer, human bone and soft tissue sarcomas, and prostate cancer. 74 – 76 This vector injected into the primary tumor might be effective in purging micrometastasis from regional lymph nodes in an orthotopic colorectal cancer model. 77 OBP-301 enhances the sensitivity of various cancers to chemotherapy; eg, lung cancer, ovarian cancer.…”

Section: Therapeutic Potential and Clinical Utility Of The Replicatiomentioning

confidence: 99%

Clinical utility of recombinant adenoviral human p53 gene therapy: current perspectives

Chen

Zhang²,

et al. 2014

OTT

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Gene therapy has promised to be a highly effective antitumor treatment by introducing a tumor suppressor gene or the abrogation of an oncogene. Among the potential therapeutic transgenes, the tumor suppressor gene p53 serves as an attractive target. Restoration of wild-type p53 function in tumors can be achieved by introduction of an intact complementary deoxyribonucleic acid copy of the p53 gene using a suitable viral vector, in most cases an adenoviral vector (Adp53). Preclinical in vitro and in vivo studies have shown that Adp53 triggers a dramatic tumor regression response in various cancers. These viruses are engineered to lack certain early proteins and are thus replication defective, including Gendicine, SCH-58500, and Advexin. Several types of tumor-specific p53-expressing conditionally replicating adenovirus vectors (known as replication-competent CRAdp53 vectors) have been developed, such as ONYX 015, AdDelta24-p53, SG600-p53, OBP-702, and H101. Various clinical trials have been conducted to investigate the safety and efficiency of these adenoviral vectors. In this review we will talk about the biological mechanisms, clinical utility, and therapeutic potentials of the replication-deficient Adp53-based and replication-competent CRAdp53-based gene therapy.

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Telomerase-specific virotherapy in an animal model of human head and neck cancer

Abstract: Telomerase-specific replication-competent adenovirus, Telomelysin (OBP-301), has a human telomerase reverse transcriptase promoter that regulates viral replication and efficiently kills human cancer cells.

Cited by 10 publications

References 27 publications

Use of telomelysin (OBP-301) in mouse xenografts of human head and neck cancer

Use of telomelysin (OBP-301) in mouse xenografts of human head and neck cancer

Antitumor effects of telomerase-specific replication-selective oncolytic viruses for adenoid cystic carcinoma cell lines

Clinical utility of recombinant adenoviral human p53 gene therapy: current perspectives

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