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Press Release
Targeted
Immune Cells Shrink Tumors in Mice
Clinical trials are
being developed to investigate this approach in patients
with mesothelioma and ovarian cancer.
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.
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. 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
study collaborator. 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 new 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."
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.
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.
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).
Contact:
NCI
Office of Media Relations
301-406-6641
University of Pennsylvania
Karen
Kreeger
215-349-5658
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