Vaccinia virus GLV-1h153 is a novel agent for detection and effective local control of positive surgical margins for breast cancer

Abstract

IntroductionSurgery 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.MethodsGLV-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.ResultsViral 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).ConclusionsThis 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.

The Sodium/Iodide Symporter (NIS): Molecular Physiology and Preclinical and Clinical Applications

“…VV carrying NIS was used as an imaging tool to identify positive surgical margins of breast cancer in a murine model (150). Ninety percent of the tumors xenografted into the mammary fat pad were surgically resected and subsequently injected with VV-NIS in the surgical wound.…”

“…Ninety percent of the tumors xenografted into the mammary fat pad were surgically resected and subsequently injected with VV-NIS in the surgical wound. 124 I − microPET images showed that fewer than 10% of cells were still alive five days after treatment (150). VV carrying NIS was also successfully used in a combined therapy with radionuclides, exploiting the induced capability of the infected cells to actively accumulate 131 I − , as reported by Gholami et al (151) for anaplastic thyroid tumors that had lost their ability to accumulate I − and by Mansfield et al (152) for prostate cancer.…”

A novel vaccinia virus with dual oncolytic and anti-angiogenic therapeutic effects against triple-negative breast cancer

“…Fluorescent imaging can assist clinicians by detecting viral distribution in order to monitor therapeutic effects via tumor localization and drug toxicity. Our laboratory has previously shown that this viral reporter gene may be utilized as a predictor of response to therapy [10] and to monitor invasion and metastatic spread in TNBC cells [11]. Lastly, we note that oncolytic vaccinia therapy is a safe approach as it has been demonstrated to be safely given to millions of patients during the smallpox eradication.…”

“…In our laboratory, we have previously shown that vaccinia virus can infect, replicate in, and kill cancer cells, including anaplastic thyroid [7], pancreatic [8], gliomas [9], and breast [10], specifically including TNBC [11]. GLV-1h164 is an oncolytic vaccinia virus strain that contains the single-chain antibody sequence for GLAF-2, an antibody directed against VEGF.…”

Viruses as nanomedicine for cancer

“…GLV-1h164 was generated using an scAb for VEGF to suppress VEGF activity, and its efficacy was tested in TNBC cell lines and an orthotopic murine model. 55 The therapeutic efficacy of GLV-1h153 that expresses NIS was also evaluated in prostate cancer models as different combinations with external beam radiotherapy and NIS-mediated radioiodine therapy. Human prostate cancer cell lines -PC3, DU145, LNCaP, and WPMY-1 were used as in vitro models.…”