Researchers have generated altered immune cells that are able to shrink, and in some cases eradicate, large tumors in mice. The immune cells target mesothelin, a protein that is highly expressed, or translated in large amounts from the mesothelin gene, on the surface of several types of cancer cells. The approach, developed by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, and at the University of Pennsylvania School of Medicine, shows promise in the development of immunotherapies for certain tumors. The study appeared online the week of Feb. 9, 2009, in the Proceedings of the National Academy of Sciences. In a more recent study, appearing online May 5, 2009, in Molecular Cancer Therapeutics, NCI researchers developed a human antibody against mesothelin that shows potential, in laboratory experiments, for cancer treatment and diagnosis.

Expression of mesothelin is normally limited to the cells that make up the protective lining (mesothelium) of the body's cavities and internal organs. However, the protein is abundantly expressed by nearly all pancreatic cancers and mesotheliomas and by many ovarian and non-small-cell lung cancers. Elevated levels of mesothelin have been reported in the blood of workers exposed to asbestos several years before tumors are detected and increased levels have been found in patients with mesothelin-expressing forms of cancer. Although the biological function of mesothelin is not known for certain, it is thought to play a role in the growth and metastatic spread of the cancers that express it.

"Since tumor cells are derived from the body's normal cells, the immune system often does not recognize tumor molecules as dangerous or foreign and does not mount a strong attack against them," said Ira Pastan, M.D., chief of the Laboratory of Molecular Biology in NCI's Center for Cancer Research, a collaborator on both studies. Moreover, even though it is possible to genetically engineer immune system cells to recognize molecules on tumor cells, most of the molecules found on tumor cells are also found on normal cells. But, Pastan notes, "Mesothelin is a promising candidate for generating tumor-targeting T cells, given its limited expression in normal tissues and high expression in several cancers."

Previous laboratory research has shown that certain immune system cells, called T cells, can kill tumor cells that express mesothelin. In addition, studies in both animals and humans have shown that antibodies directed against mesothelin protein can shrink tumors.

In the NCI-Penn Medicine study, the research team genetically engineered human T cells to target human mesothelin. To produce them, a modified virus was used as a delivery vehicle, or vector, to transfer synthetic genes to T cells. These genes directed the production of hybrid, or chimeric, proteins that can recognize and bind to mesothelin and consequently stimulate the proliferation and cell-killing activity of the T cells. In laboratory studies, the team found that the engineered T cells proliferated and secreted multiple cytokines when exposed to mesothelin. Cytokines are proteins that help control immune functions. The cells also expressed proteins that made them resistant to the toxic effects of tumors and their surrounding tissues.

To study the effects of the engineered T cells on tumor tissue, the researchers implanted human mesothelioma cells underneath the skin of mice. About six weeks later, when tumors had formed and progressed to an advanced stage, the engineered T cells were administered to the mice. Direct injection of the T cells into tumors or into veins of the mice resulted in disappearance or shrinkage of the tumor.

"Based on the size of the tumors and the number of cells administered, we estimate that one mesothelin-targeted T cell was able to kill about 40 tumor cells," said study leader Carl H. June, M.D., professor of Pathology and Laboratory Medicine at the University of Pennsylvania School of Medicine and director of Translational Research at Penn's Abramson Cancer Center. "This finding indicates that small doses of these cells may have potential in treating patients with large tumors. Clinical trials are being developed to investigate this approach in patients with mesothelioma and ovarian cancer."

In the newer study, an NCI team led by Dimiter S. Dimitrov, Ph.D., and leading author Yang Feng, Ph.D., of NCI's Center for Cancer Research, investigated a different approach to target cancer cells expressing mesothelin. They identified a novel human antibody, called m912, by screening a large library of antibodies against mesothelin. Antibodies are proteins produced by the immune system to help identify and fight disease-causing foreign invaders called antigens, such as viruses and bacteria. Some antibodies kill antigens, while others stimulate white blood cells of the immune system to kill antigens.

The team found that m912 bound specifically to mesothelin located on the surface of laboratory-grown human cancer cells that were engineered to express mesothelin, but m912 did not bind to other cell surface proteins. In the presence of white blood cells that were obtained from the blood of healthy persons, m912 killed the mesothelin-expressing cancer cells, but m912 alone did not affect cancer cell growth. This finding indicates that m912 may contribute to the death of mesothelin-expressing cancer cells by stimulating white blood cells to attack them.

"A fully human mesothelin antibody may be a promising addition to mesothelin-related therapies currently under investigation, such as mesothelin-specific T cells," said Dimitrov. "The antibody that we indentified, m912, could have broad applications in the treatment and detection of mesothelin-expressing tumors. Its tumor killing activity could be improved by joining it to toxins or small molecule drugs. The antibody could also be used to guide carriers of anti-cancer drugs or imaging compounds to cancer cells and as an agent for detection of mesothelin in the blood of cancer patients."

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For more information on Dr. Pastan's research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5782.

For more information on Dr. June's research, please go to http://www.med.upenn.edu/camb/faculty/gt/june.html.

For more information on Dr. Dimitrov's research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5749.

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

PENN Medicine is a $3.6 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is currently ranked #4 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,700 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System (UPHS) includes its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation's top ten "Honor Roll" hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center. In addition UPHS includes a primary-care provider network; a faculty practice plan; home care, hospice, and nursing home; three multispecialty satellite facilities; as well as the Penn Medicine at Rittenhouse campus, which offers comprehensive inpatient rehabilitation facilities and outpatient services in multiple specialties.

References: Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, Varela-Rohena A , Haines KM, Heitjan DF, Albelda SM, Carroll RG, Riley JL, Pastan I, and June CH. Control of large established tumor xenografts with genetically re-targeted human T cells containing CD28 and CD137 domains. PNAS. Online the week of February 9, 2009

Feng Y, Xiao X, Zhu Z, Streaker E, Ho M, Pastan I, and Dimitrov D. A novel human monoclonal antibody that binds with high affinity to mesothelin-expressing cells and kills them by ADCC. Mol. Cancer Ther. Online May 5, 2009

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