The experimental oncolytic adenovirus telomelysin in combination with radiotherapy was safe and showed early clinical efficacy in vulnerable patients with esophageal cancer, according to results from a phase I clinical trial presented by Fujiwara et al at the American Association for Cancer Research (AACR) Annual Meeting 2019.
“Most standard therapeutic strategies for esophageal cancer, such as surgery and chemoradiotherapy, are relatively invasive, and can’t be used in certain patients, including the elderly and those with health complications,” said first study author Toshiyoshi Fujiwara, MD, PhD, Professor and Chairman in the Department of Gastroenterological Surgery at the Okayama University Graduate School of Medicine. “Our combinatorial virotherapy/radiotherapy treatment is less invasive, is applicable for vulnerable patients, and has provided extremely encouraging results.”
More About Telomelysin
Many cancer cells overexpress the enzyme telomerase, which enables their replication and proliferation, explained Dr. Fujiwara. Telomelysin is a genetically modified virus which selectively replicates in telomerase-positive cells; viral infection is therefore enriched in cancerous cells, causing cell lysis, he added. A prior phase I trial evaluating telomelysin as a monotherapy found the strategy safe and biologically active in patients with advanced solid tumors.
Because it can also disrupt pathways that control DNA repair, Dr. Fujiwara and colleagues believe that tumor cells treated with the virotherapy can be rendered sensitive to ionizing radiation, allowing for the synergy of these two therapies.
In this open-label, phase I dose-escalation trial, the investigators enrolled 13 patients with histologically confirmed esophageal cancer deemed unfit to receive standard surgery or chemotherapy; all patients were elderly and/or had complications such as pulmonary disease, cardiovascular disorders, or liver dysfunction, explained Dr. Fujiwara. Patients’ median age was 80 years.
Patients received three intratumoral injections of telomelysin (each injection ranging between 10 billion and 1 trillion viral particles) via endoscope over several weeks with concurrent radiation therapy to a total of 60 Gy. The primary and secondary endpoints were dose-limiting toxicities and objective response rate (ORR), respectively.
In all 13 patients, the ORR was 85%, which included eight complete responses and three partial responses. The clinical complete response rate—defined as endoscopically and pathologically confirmed complete disappearance of tumor in the esophagus—was 83% and 60% for patients with stage I and stage II/III disease, respectively. No patients had viable malignant cells in posttreatment biopsy specimens.
Common toxicities included fever, esophagitis, pneumonitis, anorexia, constipation, and gastroesophageal reflux. All patients developed transient and self-limiting lymphopenia, and there were no dose-limiting toxicities.
“Not only was our combinatorial therapy safe, but it induced the complete eradication of esophageal tumors in most patients,” said Dr. Fujiwara. “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.”
Histopathologic examination of posttreatment biopsies taken from patients with PR revealed infiltration of CD8-positive T cells, suggesting that this combinatorial therapy may synergize with checkpoint inhibition, Dr. Fujiwara noted.
Limitations of this study include small sample size, which is consistent with a phase I dose-escalation trial.
Disclosure: This study was sponsored by the Ministry of Education, Science, and Culture in Japan and by the Japan Agency for Medical Research and Development. The study authors’ full disclosures can be found at abstractsonline.com.
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