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.
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