“This is an exciting strategy that seems to elicit a complete
immunologic response against HER2/neu,?says the study’s lead author,
Lawrence Lachman, Ph.D., a professor in the Department of Experimental
Therapeutics. “Now that we have gone as far as we can in animal
studies, I hope this agent might be tested clinically both to treat
HER2/neu breast tumors, and to prevent them from spreading.?Up to one-third of human breast cancers are associated with
over-expression of the HER2/neu cell surface receptor protein, which
continuously “tells?the cancer cell to grow, this producing an
aggressive disease that is difficult to stop.
The drug Herceptin treats this kind of breast cancer by “plugging?these receptors with a monoclonal antibody, but this treatment
“produces only a passive and transitory immune reaction,?Lachman said.
“This vaccine, however, like many that treat microbial infections,
appears to create a memory in the immune system that produces a lasting
protective response.?The vaccine used in this study is a
“viral-vectored?approach, in which a naturally occurring virus is
re-engineered to be propagation defective but still able to function as
a delivery system for proteins from the cancer cells that are to be
targeted by the animal’s immune system.
The basis for this new va
ccine is an RNA virus called VEE, for
Venezuelan equine encephalitis, which in its natural form can cause
disease in horses.
Researchers at AlphaVax, Inc., a privately held biotechnology company
in Research Triangle Park, N.C., have deleted certain genes from the
VEE virus, thereby making it impossible for the vector version of virus
to reproduce itself, but still allowing the vector to express the
target protein. For this study, the researchers inserted the gene for
the HER2/neu protein in place of the deleted viral genes and then
packaged the virus vector into virus-like replicon particles, referred
to as “VRP-neu.?When these non-propagating particles are injected into
an animal, the vector directs the animal’s cells to make thousands of
copies of the HER2/neu growth protein, says Lachman.
In addition, the VRP-neu preferentially homes to specialized immune
system cells known as dendritic cells, and infects them. Inside,
VRP-neu produces high levels of the HER2/neu protein, which the
dendritic cells then display on the outside of their cell surface. This
is, in fact, a neat trick, says Lachman, because the function of
dendritic cells is to flag the immune system by presenting “antigen,?or pieces of a foreign invader, to activate an immune response. “So
now, the same immune system cells that rev up the immune system are
displaying HER2/neu proteins as antigens,?Lachman says.
What results is a strong response against HER2/neu that incorporates
all three arms of the immune system ¯ B cell, T cell and natural killer
cells ¯ and which creates a long-lasting immune memory primed to attack
breast cancer cells that are studded with HER2/neu proteins, he says.
In the experiments, three groups of seven mice were treated with three
injections of a vaccine. The “control?arm received a VRP vaccine that
contained an influenza protein, and the other two groups received one
of two different doses of the VRP-neu vaccine. Researchers then
implanted a HER2/neu-positive tumor into mam
mary tissue in the mice.
All of the control mice developed breast cancer but only one mouse in
each of the VRP-neu groups did. In short, 86 percent of mice that
received the vaccine were protected against the cancer. The experiment
was repeated numerous times with the same result, says Lachman.
Researchers also worked with mice that were genetically engineered to
over-express HER2/neu. These mice normally develop breast cancer in all
ten of their mammary glands by the time there are 120 days old. In this
experiment, they vaccinated the mice three times with VRP-neu, and “not
a single mouse developed a tumor,?says Lachman.
Lachman suggests the vaccine might prove helpful in keeping human
HER2/neu tumors from metastasizing, or spreading, but adds that this
notion must be tested in human clinical trials.
Lachman believes that the vaccine will address two additional safety
considerations “because it is built of RNA that cannot insert itself
into the genome, and the possibility of autoimmunity to it appears to
be low, because normal cells express very small amounts of the HER2/neu
Source:M.D. Anderson Cancer Center
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