Virotherapy, radiotherapy combination shows activity in esophageal cancer

Toshiyoshi Fujiwara

ATLANTA — The experimental oncolytic adenovirus telomelysin, or OBP-301, in combination with radiotherapy, demonstrated feasibility and conferred clinical benefit among patients with esophageal cancer deemed unfit for standard surgery or chemotherapy, according to results from a phase 1 dose-escalation trial presented at American Association for Cancer Research Annual Meeting.

OBP-301 (Oncolys BioPharma) is an attenuated type-5 adenovirus that contains the human telomerase reverse transcriptase promoter to selectively replicate in cells positive for telomerase, an enzyme overexpressed by many cancer cells. The virotherapy leads to enrichment of viral infection in the cancerous cells, causing cell lysis. A prior phase 1 trial showed OBP-301 monotherapy appeared safe and demonstrated activity in patients with advanced solid tumors.

Tumor cells treated with virotherapy may also be more sensitive to ionizing radiation, because OBP-301 disrupts pathways that control DNA repair, a preclinical study showed.

Thus, Toshiyoshi Fujiwara, MD, PhD, professor and chairman in the department of gastroenterological surgery at Okayama University Graduate School of Medicine, and colleagues sought to evaluate the feasibility, efficacy and pharmacokinetics of using OBP-301 in combination with radiotherapy among 13 patients (median age, 79.7 years; range, 53-92; men, n = 10) with esophageal cancer. The patients all were deemed unfit for standard treatments, as they were elderly and had complications such as pulmonary disease, cardiovascular disease or liver disfunction.

Patients received the virus through intratumor needle injection of the primary tumor on days 1, 18 and 32. Seven patients received 10e10 virus particles of OBP-301, and three each received 10e11- and 10e12-virus particle doses.

Patients received concurrent radiation treatment over 6 weeks beginning on day 4, for a total of 60 Gy.

Dose-limiting toxicities served as the primary endpoint. Objective response rate served as a secondary endpoint.

Five of the six patients treated at the highest two doses had detectable viral DNA, but it was rarely observed in their gargle, saliva and urine.

Eight patients achieved a local complete response and three achieved a partial response, for an ORR of 84.6%. No patient had viable malignant cells in biopsy specimens following treatment.

The three partial responders showed “massive infiltration” of CD8-positive cells in their posttreatment specimens, according to the researchers, which may indicate that this regimen would have a synergistic effect with checkpoint inhibitor therapy.

Researchers observed clinical complete response — defined as endoscopically and pathologically confirmed complete disappearance of tumor in the esophagus — among 80% of patients with stage I disease and 66.7% with stage II/stage III disease.

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The most common grade 1 and grade 2 toxicities included fever, esophagitis, pneumonitis, anorexia, constipation and gastroesophageal reflux.

Researchers noted that all patients developed a transient, self-limited lymphopenia, but no dose-limiting toxicities occurred.

The study is limited by its small population size.

“Not only was our combinatorial therapy safe, but it induced the complete eradication of esophageal tumors in most patients,” Fujiwara said in a press release. “These preliminary results indicate that there may be less-invasive treatment options available for [patients with] esophageal cancer who are unable to receive standard therapies for their disease.” – by Alexandra Todak

Reference:

Fujiwara T, et al. Abstract CT185. Presented at: AACR Annual Meeting; March 29-April 3, 2019; Atlanta.

Disclosures: The Ministry of Education, Science and Culture in Japan and the Japan Agency for Medical Research and Development sponsored this study. Fujiwara reports a consultant role with Oncolys BioPharma. Please see the abstract for all other authors’ relevant financial disclosures.