Group Designs DNA Vaccine that Inhibits Growth of Cancerous
Tumors
A group of researchers at The Scripps Research Institute
(TSRI) have developed a novel DNA vaccine that helps the body
resist the growth of cancerous tumors by choking off the tumors'
blood supply. Not yet tested in humans and still in preliminary
development, their vaccine has the potential to treat many
types of cancer, and it may provide a new strategy for the
rational design of cancer therapies.
"We stimulate the immune system to recognize proliferating
blood vessels in the tumor vasculature and to recruit killer
T cells to destroy these vessels," explains TSRI Immunology
Professor Ralph Reisfeld, who conducted the study with Research
Associate Andreas G. Niethammer, and others. "Deprived of
its blood supply, the tumor [eventually dies]."
Niethammer, Reisfeld, and their collaborators describe their
successful pre-clinical studies with the vaccine in an article
to be published next month in the journal Nature Medicine.
Two Approaches to Treating Cancer
Cancer is not a single disease, but rather over a hundred
diseases caused by various sorts of mutations inside various
cells in various tissues. Some mutations upregulate genes,
increasing the expression of metalloproteinases for instance;
others downregulate them, shutting off production of receptor
proteins.
After certain mutations occur, a cancer cell grows out of
control, dividing over and over and forming a solid tumor.
Cancer tumors often damage the tissues where they are located
and some can metastasize and migrate through the bloodstream—the
malignant carcinoma that claims so many lives every year.
In recent years, some novel approaches to treating cancer
have generated interest in scientific circles and society
at large.
One of these approaches to is to try to block the process
of angiogenesis, the formation of new blood vessels that bring
necessary nutrients and oxygen to the hungry tumor cells.
Block angiogenesis, the thinking goes, and you can starve
a tumor—like drying out a lake by diverting all its tributaries.
The second approach involves attacking the tumor cells directly
with a technique known as active immunotherapy. Active immunotherapy
involves giving the immune system a push to start killing
cancer cells by presenting the so-called killer T cells with
tumor-specific antigen. Antigens are markers—proteins
on the surface of a cancer cell, for instance—that are
used by the immune system to distinguish one cell from another.
Once a killer T cell is presented with the specific antigen,
it is stimulated to expand and selectively attack cells that
display that antigen. Since cancer cells are originally "self"
cells, the trick is to find some antigen that they display,
but which normal cells in the body do not. Fortunately, the
mutations that cause cancer often cause such antigens to appear
on the surface of cancer cells. Sometimes, these antigens
are overexpressed on cancer cells, decorating them much more
than normal cells, and sometimes the antigens are expressed
only on cancer cells. But in any case, when the immune system
is stimulated to specifically attack cells with those antigens,
the cancer cells can no longer hide behind their "self" facade.
The drawback to immunotherapy is that tumor cells are often
very different from one another, confounding attempts to find
a single antigen to broadly attack various cancer tumors.
Compounding this problem is that even the original tumor can
acquire emergent resistance by mutating—as cancer cells
often do—and downregulate the target antigens, becoming
invisible to the passing killer T cells.
Similarly, anti-angiogenic approaches are complicated by
the fact that there are many ways through which a tumor cell
can start angiogenesis. Blocking one may simply cause the
tumor cells to use another.
But by combining the two approaches, the TSRI team seems
to have solved both problems.
Anti-Angiogenic DNA Vaccines—A New Approach
The solution that Niethammer and Reisfeld employed was to
target not the tumor cells themselves but the endothelial
cells that proliferate to form new blood vessels. Unlike the
tumor cells, which readily mutate to resist treatment, the
endothelial cells are not prone to mutations and therefore
represent a more stationary target.
And targeting the endothelial cells proved effective because
these cells are absolutely necessary for tumor growth, since
they provide the blood that the tumor cells need to grow.
The DNA vaccine uses an antigen "marker" known as vascular-endothelial
growth factor receptor-2 that is upregulated on endothelial
cells—particularly those that are undergoing angiogenesis
due to nearby cancer tumor growth.
This antigen DNA is inserted into a "targeting vector,"
the replication-deficient Samonella typhimurium bacteria,
which direct the DNA to lymph nodes in the gut—the so-called
Peyer's patches. Once there, the bacteria die and release
the bits of DNA, which are taken up by professional antigen-presenting
dendritic cells and macrophages. Within these cells, the DNA
is translated into protein and then presented to T cells.
Once the T cells see the growth factor receptor, they are
activated and will circulate through the bloodstream targeting
potential tumor-supporting angiogenic endothelial cells that
display it.
"We hope that these studies established a proof of concept
that may eventually contribute to the development of novel
cancer therapies," says Niethammer.
The article, "A DNA vaccine against VEGF receptor 2 prevents
effective angiogenesis and inhibits tumor growth" was authored
by Andreas G. Niethammer, Rong Xiang, Jurgen C. Becker, Harald
Wodrich, Ursula Pertl, Gabriele Karsten, Brian P. Eliceiri,
and Ralph A. Reisfeld and appears in the November 4, 2002
online edition of the journal Nature Medicine. The
article will appear in print in the December 2002 edition
of the same journal.
This work was supported by the National Institutes of Health,
the American Heart Association, the Tobacco-Related Disease
Research Program Grant, the Department of Defense, EMD Lexigen
Research Center Corp., and by fellowships through Deutsche
Krebshilfe and Deutsche Forschungsgemeinschaft.
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