Regional administration of oncolytic Echovirus 1 as a novel therapy for the peritoneal dissemination of gastric cancer

Abstract

The dissemination of malignant gastric cells to the peritoneum occurs frequently, usually as an early event in disease, and results in poor patient prognosis. Surgery and chemotherapy offer limited therapeutic success. The low-pathogenic human enterovirus, Echovirus 1 (EV1), is an oncolytic virus that selectively targets and destroys malignant prostate and ovarian cancer xenografts in vivo. Lytic EV1 infection requires the cell surface expression of alpha(2)beta(1), an integrin involved in the dissemination of gastric cancer cells to the peritoneum. Herein, we evaluated the capacity of EV1 for anti-neoplastic cell action in gastric peritoneal carcinomatosis. Flow cytometric analysis demonstrated that alpha(2)beta(1) was abundantly surface expressed on a panel of gastric cancer cell lines, rendering the majority of lines highly susceptible to in vitro lytic EV1 infection and supportive of efficient viral progeny production. A bioluminescent MKN-45-Luc SCID mouse model of peritoneal dissemination was developed to allow real-time non-invasive monitoring of peritoneal tumor burden. Employing this mouse model, we demonstrated a therapeutic dose-response for escalating oncolytic EV1 doses. Taken together, these results emphasize the exciting potential for EV1 as a single or adjunct therapy for the control of the peritoneal dissemination of gastric cancer.

Human Neonatal Fc Receptor Is the Cellular Uncoating Receptor for Enterovirus B

“…Further, echoviruses such as Echo 1, Echo 7, and Echo12 possess oncolytic activity (Haley et al, 2009;Israelsson et al, 2011;Shafren et al, 2005;Ylä -Pelto et al, 2016). RIGVIR, the Echo 7-based oncolytic drug, has been approved for clinical use in Latvia for melanoma treatment (Chumakov et al, 2012;Donin ‚ a et al, 2015).…”

Establishment of a novel method to evaluate peritoneal microdissemination and therapeutic effect using luciferase assay

“…Previous studies have used 2.0–5.0 mg luciferin i.p. injected for in vivo luciferase assay to evaluate tumor extent in the peritoneal cavity . Luciferin is thought to have low cytotoxicity for peritoneal tumor clusters analyzed by luciferase assay .…”

“…injected for in vivo luciferase assay to evaluate tumor extent in the peritoneal cavity. (14)(15)(16)(17)(18) Luciferin is thought to have low cytotoxicity for peritoneal tumor clusters analyzed by luciferase assay. (21) However, it remained unclear whether luciferin had a cytotoxic effect on colon 26-luc cells.…”

“…Luciferase‐expressing cancer cells are luminous, and the luciferase assay is useful to detect living cancer cells in the peritoneal cavity with high sensitivity and reproducibility. Previous studies have reported the effectiveness of luciferase assay in macroscopically observable peritoneal tumors . However, the assay has not been used to investigate undetectable peritoneal micrometastasis.…”

“…Previous studies have reported the effectiveness of luciferase assay in macroscopically observable peritoneal tumors. (14)(15)(16)(17)(18) However, the assay has not been used to investigate undetectable peritoneal micrometastasis. We previously reported that the adhesion of cancer cells to the peritoneum occurs within 24 h (19,20) as the first stage of peritoneal dissemination.…”