Research Shows Altered Immune Cells Target Mesothelin

Researchers at the University Of Pennsylvania School Of Medicine, under the auspices of the National Cancer Institute (NCI), a division of the National Institutes of Health, have demonstrated that genetically altered human immune cells, called T cells, have the ability to target mesothelin.

Mesothelin is a protein-like substance which can be found in normal mesothelial cells. The expression of this mesothelin is normally limited to mesothelial tissues, or the mesothelium, a protective lining of certain body cavities, notably the pleural mesothelium (containing the lungs), the pericardium (heart), the peritoneal mesothelium (abdominal cavity), the visceral mesothelium, which protects internal organs, and the tunica, containing either male or female reproductive organs.

This protein is also highly expressed in certain cancers, notably mesotheliomas, some pancreatic cancers, non-small-cell lung tumors and ovarian cancers. Researchers have not identified the precise function of mesothelin, but it is recognized as contributing to the growth and metastasis of the cancers mentioned above.

Because tumor cells stem from normal cells, the immune system frequently doesn't recognize tumor cells as alien and dangerous. Therefore, it doesn't attack them. T cells, however, prove to be an exception. Previous research has already demonstrated that T cells can destroy tumor cells that express mesothelin. Human and animal studies have also shown that antibodies can shrink the tumors associated with mesothelin protein.

The technique appears to hold out hope for developing immunotherapies for mesothelin-related tumors. The study, presented online February 9, in the Proceedings of the National Academy of Sciences, has researchers genetically engineering human T cells to target tumor cells expressing mesothelin.

The engineering was achieved via a modified virus, which injected synthetic genes into specific T cells. The process, which begins by isolating T cells, involves insertion of selected genes into a transfer vector - in this case a virus, and the subsequent transfer, via the same virus, into the T cell. The process creates hybrid, or chimerical, proteins that - once isolated via DNA probes - identify and bond to mesothelin and stimulate the T cell's immune response.

Mesothelin was chosen, according to molecular biology Chief Ira Pastin of the NCI, because of its "limited expression in normal tissues and high expression in several cancers".

After inducing tumors in mice by implanting human mesothelioma cells under the skin, the chimerical T cells were then injected. The result was shrinkage or disappearance of the tumors. From that, researchers were able to estimate that each chimerical T cell was able to eradicate about 40 tumor cells.

Clinical trials are now being developed to see if this approach will work in humans with mesotheliomas and ovarian cancers.

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