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

Gholami S, Chen CH, Belin LJ, Lou E, Fujisawa S, Antonacci C, Carew A, Chen NG, De Brot M, Zanzonico PB, Szalay AA, Fong Y - Breast Cancer Res. (2013)

Bottom Line: Administration of GLV-1h153 into the surgical wound allowed positive surgical margins to be identified via PET scanning.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.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

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GLV-1h153 kills and replicated efficiently in breast cancer cell lines in vitro. A. GLV-1h153 kills breast cancer cells in a dose-dependent fashion. Cytotoxicity data of cell lines MDA-MB-231, MDA-MB-468 and HCC38 showed less than 10% viable cells after five days of infection at an MOI of 5. Multiplicity of infection (MOI) = plaque-forming units/cell. Experiment was performed in triplicates. B. GLV-1h153 replicated efficiently in all breast cancer cell lines. All cell lines supported viral replication as assessed by the viral plaque assay. Results demonstrated that in cell line MDA-MB-468, GLV-1h153 reached the highest titer of 2.7 × 107 PFU after 96 hours of infection, representing over a 10,000-fold increase in copy numbers from the initial viral dose. The experiment was performed in triplicates.
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Figure 2: GLV-1h153 kills and replicated efficiently in breast cancer cell lines in vitro. A. GLV-1h153 kills breast cancer cells in a dose-dependent fashion. Cytotoxicity data of cell lines MDA-MB-231, MDA-MB-468 and HCC38 showed less than 10% viable cells after five days of infection at an MOI of 5. Multiplicity of infection (MOI) = plaque-forming units/cell. Experiment was performed in triplicates. B. GLV-1h153 replicated efficiently in all breast cancer cell lines. All cell lines supported viral replication as assessed by the viral plaque assay. Results demonstrated that in cell line MDA-MB-468, GLV-1h153 reached the highest titer of 2.7 × 107 PFU after 96 hours of infection, representing over a 10,000-fold increase in copy numbers from the initial viral dose. The experiment was performed in triplicates.

Mentions: GLV-1h153 killed all TNBC cell lines effectively in a dose-dependent fashion (Figure 2A). At an MOI of 5, GLV-1h153 achieved near-complete cell kill in all cell lines by Day 5. At lower viral concentrations (MOI 1), there was still significant viral potency to MDA-MB-468 and HCC38 with greater than 92% and 67% cytotoxicity effect, respectively. Survival curves indicate time-dependent cell kill in all cell lines as expected from the results of the viral infectivity assay and GFP expression.


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

Gholami S, Chen CH, Belin LJ, Lou E, Fujisawa S, Antonacci C, Carew A, Chen NG, De Brot M, Zanzonico PB, Szalay AA, Fong Y - Breast Cancer Res. (2013)

GLV-1h153 kills and replicated efficiently in breast cancer cell lines in vitro. A. GLV-1h153 kills breast cancer cells in a dose-dependent fashion. Cytotoxicity data of cell lines MDA-MB-231, MDA-MB-468 and HCC38 showed less than 10% viable cells after five days of infection at an MOI of 5. Multiplicity of infection (MOI) = plaque-forming units/cell. Experiment was performed in triplicates. B. GLV-1h153 replicated efficiently in all breast cancer cell lines. All cell lines supported viral replication as assessed by the viral plaque assay. Results demonstrated that in cell line MDA-MB-468, GLV-1h153 reached the highest titer of 2.7 × 107 PFU after 96 hours of infection, representing over a 10,000-fold increase in copy numbers from the initial viral dose. The experiment was performed in triplicates.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672815&req=5

Figure 2: GLV-1h153 kills and replicated efficiently in breast cancer cell lines in vitro. A. GLV-1h153 kills breast cancer cells in a dose-dependent fashion. Cytotoxicity data of cell lines MDA-MB-231, MDA-MB-468 and HCC38 showed less than 10% viable cells after five days of infection at an MOI of 5. Multiplicity of infection (MOI) = plaque-forming units/cell. Experiment was performed in triplicates. B. GLV-1h153 replicated efficiently in all breast cancer cell lines. All cell lines supported viral replication as assessed by the viral plaque assay. Results demonstrated that in cell line MDA-MB-468, GLV-1h153 reached the highest titer of 2.7 × 107 PFU after 96 hours of infection, representing over a 10,000-fold increase in copy numbers from the initial viral dose. The experiment was performed in triplicates.
Mentions: GLV-1h153 killed all TNBC cell lines effectively in a dose-dependent fashion (Figure 2A). At an MOI of 5, GLV-1h153 achieved near-complete cell kill in all cell lines by Day 5. At lower viral concentrations (MOI 1), there was still significant viral potency to MDA-MB-468 and HCC38 with greater than 92% and 67% cytotoxicity effect, respectively. Survival curves indicate time-dependent cell kill in all cell lines as expected from the results of the viral infectivity assay and GFP expression.

Bottom Line: Administration of GLV-1h153 into the surgical wound allowed positive surgical margins to be identified via PET scanning.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.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

Show MeSH
Related in: MedlinePlus