Gene therapy using therapeutic and diagnostic recombinant oncolytic vaccinia virus GLV-1h153 for management of colorectal peritoneal carcinomatosis.

Abstract

BACKGROUND:

Peritoneal carcinomatosis (PC) is a terminal progression of colorectal cancer (CRC). Poor response to cytoreductive operation and chemotherapy coupled with the inability to reliably track disease progression by the use of established diagnostic methods, make this a deadly disease. We examined the effectiveness of the oncolytic vaccinia virus GLV-1h153 as a therapeutic and diagnostic vehicle. We believe that viral expression of the human sodium iodide transporter (hNIS) provides both real-time monitoring of viral therapy and effective treatment of colorectal peritoneal carcinomatosis (CRPC).

METHODS:

Infectivity and cytotoxic effect of GLV-1h153 on CRC cell lines was assayed in vitro. Viral replication was examined by standard viral plaque assays. Orthotopic CRPC xenografts were generated in athymic nude mice and subsequently administered GLV-1h153 intraperitoneally. A decrease in tumor burden was assessed by mass. Orthotopic tumors were visualized by single-photon emission computed tomography/computed tomography after Iodine ((131)I) administration and by fluorescence optical imaging.

RESULTS:

GLV-1h153 infected and killed CRC cells in a time- and concentration-dependent manner. Viral replication demonstrated greater than a 2.35 log increase in titer over 4 days. Intraperitoneal treatment of orthotopic CRPC xenografts resulted in a substantial decrease in tumor burden. Infection of orthotopic xenografts was therapeutic and facilitated monitoring by (131)I-single-photon emission computed tomography/computed tomography via expression of hNIS in infected tissue.

CONCLUSION:

GLV-1h153 kills CRC in vitro effectively and decreases tumor burden in vivo. We demonstrate that GLV-1h153 can be used as an agent to provide accurate delineation of tumor burden in vivo. These findings indicate that GLV-1h153 has potential for use as a therapeutic and diagnostic agent in the treatment of CRPC.

• Authors: Clarisse Eveno, Kelly Mojica, Justin W Ady, Daniel L J Thorek, Valerie Longo, Laurence J Belin, Sepideh Gholami, Clark Johnsen, Pat Zanzonico, Nanhai Chen, Tony Yu, Aladar A Szalay, Yuman Fong
• Journal: Surgery (Surgery) Vol. 157 Issue 2 Pg. 331-7 (Feb 2015) ISSN: 1532-7361 [Electronic] United States
• PMID: 25616946 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Iodine Radioisotopes
• Radiopharmaceuticals
• Recombinant Proteins
• Symporters
• Green Fluorescent Proteins
• sodium-iodide symporter

Topics

• Animals
• Cell Line, Tumor
• Colorectal Neoplasms (pathology, therapy)
• Disease Progression
• Gene Expression
• Green Fluorescent Proteins (genetics)
• Humans
• Iodine Radioisotopes
• Mice
• Mice, Nude
• Neoplasm Seeding
• Oncolytic Virotherapy (methods)
• Oncolytic Viruses (genetics)
• Peritoneal Neoplasms (pathology, secondary, therapy)
• Radiopharmaceuticals
• Recombinant Proteins (genetics)
• Symporters (genetics)
• Tomography, Emission-Computed, Single-Photon
• Vaccinia virus (genetics)
• Xenograft Model Antitumor Assays