Telomerase-Specific Virotheranostics for Human Head and Neck Cancer

Kikuchi, Yuji; Watanabe, Yuichi; Onimatsu, Hideki; Kojima, Toru; Shirota, Tatsuo; Hatori, Masahito; Liu, Dong; Kyo, Satoru; Mizuguchi, Hiroyuki; Urata, Yasuo; Shintani, Satoru; Fujiwara, Toshiyoshi

doi:10.1158/1078-0432.ccr-08-2690

Cited by 27 publications

(16 citation statements)

References 24 publications

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“…The treatment field of radiotherapy includes primary tumors and regional lymph nodes. We previously showed that intratumorally injected OBP-301 expressing the GFP gene is effectively transported into the lymphatic circulation; viral replication produced GFP fluorescence signals in the metastatic lymph nodes in orthotopic human colorectal and oral cancer xenograft models (39,40). Therefore, we anticipate that intratumoral OBP-301 administration will radiosensitize both primary tumors and regional lymph nodes.…”

Section: Discussionmentioning

confidence: 99%

Telomerase-Dependent Oncolytic Adenovirus Sensitizes Human Cancer Cells to Ionizing Radiation via Inhibition of DNA Repair Machinery

et al. 2010

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The inability to repair DNA double-strand breaks (DSB) leads to radiosensitization, such that ionizing radiation combined with molecular inhibition of cellular DSB processing may greatly affect treatment of human cancer. As a variety of viral products interact with the DNA repair machinery, oncolytic virotherapy may improve the therapeutic window of conventional radiotherapy. Here, we describe the mechanistic basis for synergy of irradiation and OBP-301 (Telomelysin), an attenuated type-5 adenovirus with oncolytic potency that contains the human telomerase reverse transcriptase promoter to regulate viral replication. OBP-301 infection led to E1B55kDa viral protein expression that degraded the complex formed by Mre11, Rad50, and NBS1, which senses DSBs. Subsequently, the phosphorylation of cellular ataxia-telangiectasia mutated protein was inhibited, disrupting the signaling pathway controlling DNA repair. Thus, tumor cells infected with OBP-301 could be rendered sensitive to ionizing radiation. Moreover, by using noninvasive whole-body imaging, we showed that intratumoral injection of OBP-301 followed by regional irradiation induces a substantial antitumor effect, resulting from tumor cell-specific radiosensitization, in an orthotopic human esophageal cancer xenograft model. These results illustrate the potential of combining oncolytic virotherapy and ionizing radiation as a promising strategy in the management of human cancer. Cancer Res; 70(22); 9339-48. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

Telomerase-Dependent Oncolytic Adenovirus Sensitizes Human Cancer Cells to Ionizing Radiation via Inhibition of DNA Repair Machinery

et al. 2010

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“…We further modified OBP-301 to express the green fluorescent protein ( GFP ) gene for monitoring viral replication. The resultant adenovirus, designated OBP-401 (TelomeScan), efficiently labeled tumor cells with green fluorescence, enabling us to track viral spread in vivo 1314. Preclinical as well as clinical studies have demonstrated successful virus spread, including spread to the regional lymphatic areas, and promising antitumor effects were shown with intratumoral administration of the virus1516.…”

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confidence: 99%

Tumor-specific delivery of biologics by a novel T-cell line HOZOT

Onishi

Tazawa

Hashimoto

et al. 2016

Sci Rep

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“Cell-in-cell” denotes an invasive phenotype in which one cell actively internalizes in another. The novel human T-cell line HOZOT, established from human umbilical cord blood, was shown to penetrate a variety of human cancer cells but not normal cells. Oncolytic viruses are emerging as biological therapies for human cancers; however, efficient viral delivery is limited by a lack of tumor-specific homing and presence of pre-existing or therapy-induced neutralizing antibodies. Here, we report a new, intriguing approach using HOZOT cells to transmit biologics such as oncolytic viruses into human cancer cells by cell-in-cell invasion. HOZOT cells were successfully loaded via human CD46 antigen with an attenuated adenovirus containing the fiber protein of adenovirus serotype 35 (OBP-401/F35), in which the telomerase promoter regulates viral replication. OBP-401/F35–loaded HOZOT cells were efficiently internalized into human cancer cells and exhibited tumor-specific killing by release of viruses, even in the presence of anti-viral neutralizing antibodies. Moreover, intraperitoneal administration of HOZOT cells loaded with OBP-401/F35 significantly suppressed peritoneally disseminated tumor growth in mice. This unique cell-in-cell property provides a platform for selective delivery of biologics into human cancer cells, which has important implications for the treatment of human cancers.

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“…We previously reported that intratumoral injection of a telomerasespecific replication-competent adenovirus Telomelysin suppressed the growth of a subcutaneous xenograft tumor (10) and of lymph node metastasis of an orthotopic colorectal cancer model (17,25). Moreover, an GFP-expressing Telomelysin (OBP-301, TelomeScan) could induce tumor-specific GFP accumulation in the metastatic regions at lymph nodes (13,26), liver (27), and peritoneal cavities (28) of colorectal tumor-bearing mice. These findings strongly suggest that a TelomeKiller-based PDT strategy is a useful anticancer strategy to eliminate metastatic tumors.…”

Section: Discussionmentioning

confidence: 99%

Targeted Photodynamic Virotherapy Armed with a Genetically Encoded Photosensitizer

Takehara

Tazawa

Okada

et al. 2016

Molecular Cancer Therapeutics

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Photodynamic therapy (PDT) is a minimally invasive antitumor therapy that eradicates tumor cells through a photosensitizermediated cytotoxic effect upon light irradiation. However, systemic administration of photosensitizer often makes it difficult to avoid a photosensitive adverse effect. The red fluorescent protein KillerRed generates reactive oxygen species (ROS) upon green light irradiation. Here, we show the therapeutic potential of a novel tumor-specific replicating photodynamic viral agent (TelomeKiller) constructed using the human telomerase reverse transcriptase (hTERT) promoter. We investigated the lightinduced antitumor effect of TelomeKiller in several types of human cancer cell lines. Relative cell viability was investigated using an XTT assay. The in vivo antitumor effect was assessed using subcutaneous xenografted tumor and lymph node metastasis models. KillerRed accumulation resulted in ROS generation and apoptosis in light-irradiated cancer cells. Intratumoral injection of TelomeKiller efficiently delivered the KillerRed protein throughout the tumors and exhibited a long-lasting antitumor effect with repeated administration and light irradiation in mice. Moreover, intratumorally injected TelomeKiller could spread into the regional lymph node area and eliminate micrometastasis with limited-field laser irradiation. Our results suggest that KillerRed has great potential as a novel photosensitizer if delivered with a tumor-specific virus-mediated delivery system. TelomeKillerbased PDT is a promising antitumor strategy to efficiently eradicate tumor cells.

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Telomerase-Specific Virotheranostics for Human Head and Neck Cancer

Cited by 27 publications

References 24 publications

Telomerase-Dependent Oncolytic Adenovirus Sensitizes Human Cancer Cells to Ionizing Radiation via Inhibition of DNA Repair Machinery

Telomerase-Dependent Oncolytic Adenovirus Sensitizes Human Cancer Cells to Ionizing Radiation via Inhibition of DNA Repair Machinery

Tumor-specific delivery of biologics by a novel T-cell line HOZOT

Targeted Photodynamic Virotherapy Armed with a Genetically Encoded Photosensitizer

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