Targeted Immune Cells Shrink Tumors in Mice
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 bodyís 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 bodyís 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 NCIís 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, ďMesothelin 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
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
"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. Pastanís research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5782.
For more information on Dr. Juneís research, please go to http://www.med.upenn.edu/camb/faculty/gt/june.html.
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Reference: 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.