Vaccinia virus GLV-1h153 is a novel agent for detection and effective local control of positive surgical margins for breast cancer
- Equal contributors
1 Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
2 Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA
3 Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
4 Department of Radiation Oncology, Rebecca & John Moores Comprehensive Cancer Center, University of California, 9500 Gilman Drive, San Diego, CA 92093, USA
5 Genelux Corporation, 3030 Bunker Hill Street, San Diego, CA 92109, USA
6 Departments of Medical Physics and Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
7 Rudolf Virchow Center for Experimental Biomedicine, Department of Biochemistry and Institute for Molecular Infection Biology, University of Würzburg, Sanderring 2, Würzburg, 97074, Germany
Breast Cancer Research 2013, 15:R26 doi:10.1186/bcr3404Published: 18 March 2013
Surgery is currently the definitive treatment for early-stage breast cancer. However, the rate of positive surgical margins remains unacceptably high. The human sodium iodide symporter (hNIS) is a naturally occurring protein in human thyroid tissue, which enables cells to concentrate radionuclides. The hNIS has been exploited to image and treat thyroid cancer. We therefore investigated the potential of a novel oncolytic vaccinia virus GLV1h-153 engineered to express the hNIS gene for identifying positive surgical margins after tumor resection via positron emission tomography (PET). Furthermore, we studied its role as an adjuvant therapeutic agent in achieving local control of remaining tumors in an orthotopic breast cancer model.
GLV-1h153, a replication-competent vaccinia virus, was tested against breast cancer cell lines at various multiplicities of infection (MOIs). Cytotoxicity and viral replication were determined. Mammary fat pad tumors were generated in athymic nude mice. To determine the utility of GLV-1h153 in identifying positive surgical margins, 90% of the mammary fat pad tumors were surgically resected and subsequently injected with GLV-1h153 or phosphate buffered saline (PBS) in the surgical wound. Serial Focus 120 microPET images were obtained six hours post-tail vein injection of approximately 600 μCi of 124I-iodide.
Viral infectivity, measured by green fluorescent protein (GFP) expression, was time- and concentration-dependent. All cell lines showed less than 10% of cell survival five days after treatment at an MOI of 5. GLV-1h153 replicated efficiently in all cell lines with a peak titer of 27 million viral plaque forming units (PFU) ( <10,000-fold increase from the initial viral dose ) by Day 4. Administration of GLV-1h153 into the surgical wound allowed positive surgical margins to be identified via PET scanning. In vivo, mean volume of infected surgically resected residual tumors four weeks after treatment was 14 mm3 versus 168 mm3 in untreated controls (P < 0.05).
This is the first study to our knowledge to demonstrate a novel vaccinia virus carrying hNIS as an imaging tool in identifying positive surgical margins of breast cancers in an orthotopic murine model. Moreover, our results suggest that GLV-1h153 is a promising therapeutic agent in achieving local control for positive surgical margins in resected breast tumors.