Abstract

Multidisciplinary Oncolytic Virotherapy for Gastrointestinal Cancer

Toshiyoshi Fujiwara, Professor & Chairman, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

Telomelysin (OBP-301) is an attenuated oncolytic adenovirus, in which the telomerase promoter drives expression of E1 genes. Telomelysin causes selective replication and lysis of a variety of human cancer cells, and also inhibits the repair of radiation-induced DNA double-strand breaks, leading to radiosensitization. A phase I study has confirmed the safety and biological activity of Telomelysin alone in patients with advanced solid tumors in the US. To further determine the feasibility, efficacy, and pharmacokinetics of Telomelysin in combination with radiotherapy, an investigator-driven clinical study was designed. Patients with histologically confirmed esophageal cancer who were not eligible for surgery or chemotherapy were enrolled into this study. Study treatment consisted of intratumoral needle injections of Telomelysin on days 1, 18, and 32 of treatment. Radiation therapy was administered concurrently over 6 weeks, beginning on day 4, to a total of up to 60 Gy. Virus administration was performed by intratumoral injection of the primary tumor through a flexible endoscope. Patients receive escalating doses of Telomelysin (10¹⁰ to 10¹² virus particles [vp]). Seven, three, and three patients were enrolled and treated in the cohorts with 10¹⁰, 10¹¹, and 10¹² vp of Telomelysin, respectively. The patients comprised 10 males and 3 females, with median age of 79.7 years (range, 53 to 92 years). Common grade 1 and 2 toxicities included fever, esophagitis, pneumonitis, anorexia, constipation, and gastroesophageal reflux disease. All patients developed a transient, self-limited lymphopenia. Objective responses were complete response (CR) in 4, 2, and 2 patients in cohort 1, 2, and 3, respectively; all of them exhibited pathologically no viable malignant cells in biopsy specimens. Histopathologic examination in post-treatment specimens showed massive infiltration of CD8⁺ cells in 3 partially responded tumors. Multiple courses of endoscopic Telomelysin injection with radiotherapy were feasible and well tolerated in patients with esophageal cancer, and appeared to provide clinical benefit.