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Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) Transfected Whole Cell Vaccine Impedes the Development of Esophageal Cancer in Rats with Infiltration By CD4 and Cd8 Positive Cells
Tomoharu Miyashita*1, Todd D. Armstrong2, Jiaai Wang1, Furhawn Shah1, Michael K. Gibson3, Kiyoshi Yoshimura3, Xianji Zhang1, Guy Marti1, Mark Duncan1, Elizabeth a. Montgomery4, Elizabeth M. Jaffee2, John W. Harmon1
1Surgery, Johns Hopkins University, Baltimore, MD; 2Hematology/Oncology, Johns Hopkins University, Baltimore, MD; 3Oncology, Johns Hopkins University, Baltimore, MD; 4Pathology, Johns Hopkins University, Baltimore, MD

Introduction
Our aim is to develop a tumor vaccine to protect individuals with Barrett’s esophageal dysplasia from developing esophageal cancer. Initially, we have developed a whole-cell esophageal cancer vaccine in the rat. First we assessed the vaccine’s ability to impede the growth of esophageal cancer cells implanted subcutaneously in rats. Then we assessed it in the more clinically relevant rat surgical reflux model.
Methods
We established an adenosquamous cell line from reflux-induced esophageal cancers in a rat model. The cell lines shared molecular characteristics of human esophageal cancer cells, confirmed by microarray and karyotyping (J Surg Res. 2006 Jul;134(1):1-9; J Thorac Cardiovasc Surg, in press). They also expressed MHC class I molecules. The transfected cell line produced GM-CSF at a rate of 55 ng/24 hours/1×10^6 cells as measured by ELISA.
Implantation Experiment
The growth of subcutaneous tumor implants in Sprague Dawley rats was assessed. Rats were vaccinated with 3 x 10^7 of irradiated vaccine cells secreting GM-CSF or a PBS control. The implant consisted of 1.5 x 10^7 cultured tumor cells with MatrigelTM on day 0. Rats were vaccinated 7 days prior to the start of the experiment. Immunochistochemistry for CD4 and CD8a was performed with mouse anti-rat monoclonal antibody. (BD Biosciences,San Jose, CA)
Reflux Model Experiment
After learning about the success of the GM-CSF whole-cell vaccine, a rat reflux model was created by performing a total gastrectomy on the rats, followed by an esophago-jejunostomy. Rats were vaccinated 4, 6, 14 and 16 weeks after surgery with 3 ×10^7 irradiated vaccine cells secreting GM-CSF or PBS vehicle. All surviving animals were sacrificed 40 weeks after surgery and their esophagi were examined grossly and histologically.ResultsImplantation ExperimentWhen rats were vaccinated prior to implantation, all tumors on vaccinated rats disappeared entirely by day 14. On the other hand, tumors on PBS control rats became progressively larger (ANOVA:p < 0.001). Immunohistochemisty showed robust infiltration of CD8a+ and CD4+ T-cells around the implanted tumor in the vaccine group, but not in the control.
Reflux Model Experiment
Fifteen of 16 animals in the control group developed esophageal cancer 94% (15/16). However, the vaccine group had an incidence of cancer of only 25% (4/16). The vaccine group had a significantly lower chance of developing cancer than the control group (X2, p<0.001).
Conclusions
The GM-CSF esophageal cancer vaccine warrants further investigation for potential clinical use in treating and/or preventing esophageal cancer.


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