A phase I clinical trial was conducted to determine the clinical safety of Telomelysin, a human telomerase reverse transcriptase (hTERT) promoter driven modified oncolytic adenovirus, in patients with advanced solid tumors. A single intratumoral injection (IT) of Telomelysin was administered to three cohorts of patients (1 x 10(10), 1 x 10(11), 1 x 10(12) viral particles). Safety, response and pharmacodynamics were evaluated. Sixteen patients with a variety of solid tumors were enrolled. IT of Telomelysin was well tolerated at all dose levels. Common grade 1 and 2 toxicities included injection site reactions (pain, induration) and systemic reactions (fever, chills). hTERT expression was demonstrated at biopsy in 9 of 12 patients. Viral DNA was transiently detected in plasma in 13 of 16 patients. Viral DNA was detectable in four patients in plasma or sputum at day 7 and 14 post-treatment despite below detectable levels at 24 h, suggesting viral replication. One patient had a partial response of the injected malignant lesion. Seven patients fulfilled Response Evaluation Criteria in Solid Tumors (RECIST) definition for stable disease at day 56 after treatment. Telomelysin was well tolerated. Evidence of antitumor activity was suggested.

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that is related to asbestos exposure. MPM is characterized by rapid and diffuse local growth in the thoracic cavity, and it has a poor prognosis because it is often refractory to conventional therapy. Although MPM is an extraordinarily challenging disease to treat, locoregional virotherapy may be useful against this aggressive disease because of the accessibility by intrapleural virus delivery. In this study, we show that telomerasespecific, replication-selective adenovirus OBP-301 can efficiently infect and kill human mesothelioma cells by viral replication. Intrathoracic administration of virus significantly reduced the number and size of human mesothelioma tumors intrathoracically implanted into nu/nu mice. A high-definition, fluorescence optical imaging system with an ultra-thin, flexible fibered microprobe clearly detected intracellular replication of green fluorescent protein-expressing oncolytic virus in intrathoracically established mesothelioma tumors. As the extracellular matrix (ECM) may contribute to the physiological resistance of a solid tumor by preventing the penetration of therapeutic agents (including oncolytic viruses), we also examined whether the co-expression of heparanase, an endoglucuronidase capable of specifically degrading heparan sulfate, that influences the physiological barrier to macromolecule penetration, can modify the permeability of the ECM, resulting in profound therapeutic efficacy. Co-injection of OBP-301 and a replication-defective adenovirus (Ad-S/hep)-expressing heparanase resulted in more profound antitumor effects without apparent toxicity in an orthotopic pleural dissemination model. Our results suggest that intrathoracic dual virotherapy with telomerase-specific oncolytic adenovirus in combination with heparanase-expressing adenovirus may be efficacious in the prevention and treatment of pleural dissemination of human malignant mesothelioma.

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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.

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...