Abstract
3572 Background: Telomerase activation is considered to be a critical step in carcinogenesis and its activity is closely correlated with human telomerase reverse transcriptase (hTERT) expression. We constructed an adenovirus 5 vector (OBP-301 [Telomelysin]), in which the hTERT promoter drives expression of E1A and E1B genes linked with an IRES. OBP-301 causes selective replication and lysis of a variety of human cancer cells, and has shown preclinical efficacy against human tumor xenografts. A phase I study was designed to determine the feasibility and to characterize the pharmacokinetics of OBP-301 in patients with advanced solid tumors. Methods: Patients with histologically confirmed advanced solid tumors were enrolled into this phase I trial. Nine patients received escalating dose levels of OBP-301 (1 x 1010 to 1 x 1012 virus particles [vp]) as monotherapy. Patients were monitored over two months for safety and tolerability, vector distribution, antibody formation, and tumor response. Virus shedding was monitored in the saliva, sputum, urine, and plasma by a quantitative DNA-PCR assay targeting the IRES sequence. Results: All patients received a single intratumoral injection of OBP-301 without dose-limiting toxicity. The primary tumor types were head and neck (n=2), breast (n=1), soft tissue (n=1), and others (n=5). Circulating OBP-301 viral genome became detectable in the plasma within 24 hours after injection in all patients except one. This dose-dependent initial peak in circulating virus was followed by a rapid decline; however, two patients received 1010 and 1012 vp showed a second peak of circulating viral DNA on day 14, suggesting OBP-301 replication in primary tumors. In contrast, no viral DNA was detected in all saliva, sputum, and urine samples except two specimens. Titers of neutralizing antibody to adenovirus collected at 28 days after injection of OBP-301 were higher than the titers at baseline in all 8 patients tested. All patients had stable disease at the day 28 assessment, although 6 patients showed 6.6 to 34% tumor size reduction. Conclusions: OBP-301 is well-tolerated and warrants further clinical studies for solid cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Oncolys BioPharma, Inc. Oncolys BioPharma, Inc. Oncolys BioPharma, Inc.
Published Version
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