Phase I trial of intratumoral administration of OBP-301, a novel telomerase-specific oncolytic virus, in patients with advanced solid cancer: Evaluation of biodistribution and immune response

Fujiwara, T.; Tanaka, Nobuyuki; Nemunaitis, John; Senzer, Neil; Tong, Alex W.; Ichimaru, Daiju; Shelby, Shaija; Hashimoto, Yuichi; Kawamura, Hikaru; Urata, Yasuo

doi:10.1200/jco.2008.26.15_suppl.3572

Cited by 11 publications

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“…Fujiwara and colleagues reported that nine patients received escalating dose levels of OBP-301 (1x10 10 to 1x10 12 v.p.) as monotherapy had stable disease at day 28 of assessment, although 6 patients showed 6.6 to 34% tumor size reduction (14). Results from current clinical trials should yield additional information on its efficacy.…”

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: Discussionmentioning

confidence: 99%

“…A phase I study of OBP-301 has been started in the US in patients with various types of progressive solid cancer, including SCCHN (14). We have previously reported that a 5-day i.t.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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“…A series of our previous studies have shown the anti-tumor effects of OBP-301 in various types of cancers, including lung and colorectal cancers both in vitro and in vivo, 16,21,22,[24][25][26][27] and a clinical trial of OBP-301 therapy as monotherapy is currently underway based on these preclinical studies. 29 However, these preclinical and clinical studies have been carried out mainly by direct injection of OBP-301 into primary tumor sites. This study is the first to test the effect of intraperitoneal administration of OBP-301.…”

Section: Discussionmentioning

confidence: 99%

Intraperitoneal administration of telomerase-specific oncolytic adenovirus sensitizes ovarian cancer cells to cisplatin and affects survival in a xenograft model with peritoneal dissemination

et al. 2009

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Despite tremendous development in chemotherapy for ovarian cancer over the past few decades, the prognosis of advanced cases with massive peritoneal dissemination is still unsatisfactory, and novel treatment modalities that can combine with chemotherapy are urgently needed. We recently developed virotherapy for solid tumors using telomerase-specific replication-selective adenoviruses (Telomelysin: OBP-301), in which the human telomerase reverse transcriptase (hTERT) gene promoter has been inserted to direct tumor-specific E1 gene expression. In this study, we investigated the anti-tumor effects of OBP-301, combined with cisplatin (CDDP), on ovarian cancer cells. In vitro treatment of SKOV3 cells with OBP-301 at a multiplicity of infection (MOI) of 0.01-100 induced significant cell death in a dose-dependent manner, with moderate cytotoxicity at an MOI of 1-10 and maximal cytotoxicity at an MOI of 100. In contrast, OBP-301 treatment of normal human cells showed no significant cell death at an MOI of 1-10 and exhibited modest cytotoxicity at an MOI of 100. The effects of low-dose CDDP at 0.5-1 mM, which induced only 20% cell death, were significantly augmented by combination with OBP-301 at an MOI of 1-10, finally achieving 40% cell death. Such enhancement of CDDP sensitivity was also observed in CDDP-resistant ovarian cancer cells. The combinatorial effects were further tested using a xenograft mouse model of SKOV3 with peritoneal dissemination. After intraperitoneal administration of OBP-301, we confirmed that injected OBP-301 fused with the green fluorescent protein (GFP) gene (OBP-401) was preferentially localized to peritoneal disseminations, as determined by fluorescence imaging. Treatment of mice with CDDP at low dose (0.5 mg kg -1 ) had modest effects, showing a 10% decrease in disseminations, whereas combination with intraperitoneal administration of OBP-301 at an MOI of 10 led to enhanced effects, achieving an approximately 80% decrease in disseminations. Kaplan-Meier analysis showed improved overall survival of mice treated with CDDP plus OBP-301 compared with CDDP alone. These findings support the therapeutic potential of intraperitoneal administration of OBP-301 to sensitize ovarian cancer cells to CDDP.

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“…Although a phase III trial showed a survival benefit with cetuximab and standard platinum-based therapy in SCCHN patients (23), some patients are exquisitely sensitive to these drugs and can develop particular and severe toxicities (24). A phase I study is currently under way in the United States to determine the feasibility and to characterize the pharmacokinetics of OBP-301 in patients with histologically proven nonresectable solid tumors (25). An interim analysis of the first 12 patients, including four SCCHN patients treated with escalating doses of OBP-301, indicates that OBP-301 virotherapy is well tolerated without any severe adverse events, suggesting that OBP-301 may be much more potent than other targeted therapies for human SCCHN in terms of specificity, efficacy, and toxicity.…”

Section: Discussionmentioning

confidence: 99%

Telomerase-Specific Virotheranostics for Human Head and Neck Cancer

Kikuchi

Watanabe

Onimatsu

et al. 2009

Clinical Cancer Research

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Purpose: Long-term outcomes of patients with squamous cell carcinoma of the head and neck (SCCHN) remain unsatisfactory despite advances in combination of treatment modalities. SCCHN is characterized by locoregional spread and it is clinically accessible, making it an attractive target for intratumoral biological therapies. Experimental Design: OBP-301is a type 5 adenovirus that contains the replication cassette in which the human telomerase reverse transcriptase promoter drives expression of the E1 genes. OBP-401 contained the replication cassette and the green fluorescent protein (GFP) gene. The antitumor effects of OBP-301 were evaluated in vitro by the sodium 30-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzene sulfonic acid hydrate assay and in vivo in an orthotopic xenograft model. Virus spread into the lymphatics was also orthotopically assessed by using OBP-401. Results: Intratumoral injection of OBP-301 resulted in the shrinkage of human SCCHN tumors orthotopically implanted into the tongues of BALB/c nu/nu mice and significantly recovered weight loss by enabling oral ingestion. 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 telomerasespecific virotherapy. Moreover, whole-body fluorescent imaging revealed that intratumorally injected OBP-401 could visualize the metastatic lymph nodes, indicating the ability of the virus to traffic to the regional lymphatic area and to selectively replicate in neoplastic lesions, resulting in GFP expression and cell death in metastatic lymph nodes. Conclusions: These results illustrate the potential of telomerase-specific oncolytic viruses for a novel therapeutic and diagnostic approach, termed theranostics, for human SCCHN.

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Phase I trial of intratumoral administration of OBP-301, a novel telomerase-specific oncolytic virus, in patients with advanced solid cancer: Evaluation of biodistribution and immune response

Cited by 11 publications

References 0 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

Intraperitoneal administration of telomerase-specific oncolytic adenovirus sensitizes ovarian cancer cells to cisplatin and affects survival in a xenograft model with peritoneal dissemination

Telomerase-Specific Virotheranostics for Human Head and Neck Cancer

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