RNA-Dendritic Cell Combo Shows
Promise As A Universal Cancer Vaccine
DURHAM, N.C. -- Researchers at Duke University Medical
Center
reported Tuesday that they have taken a significant
step forward in the
laboratory in demonstrating that a person's own immune
system may be the
best weapon they have to fight cancer.
The concoction they are testing is an unusual form of
gene therapy. Its ultimate
goal is to wipe out cancer cells and then keep the body
protected from new
cancer growth but much work remains to be completed
before such an agent
could be available.
The potential therapy, which already is being tested in
cancer patients, just
requires a sample of blood to extract white immune
cells and a few cancer
cells from which to distill the genetic material RNA.
Mixed together, the tumor
RNA produces everything the immune system needs to
launch an attack on
the cancer.
Laboratory proof of the cancer vaccine concept is
published in the April issue
of Nature Biotechnology. The research, supported by the
National Institutes
of Health and the CapCure Foundation, found that the
vaccine stimulated an
immediate and sustained assault on human cells targeted
for destruction in 15
out of 18 test tube experiments.
"This is a very powerful response compared to what has
been seen in other
cancer vaccines," said the scientist who led the study,
Eli Gilboa, research
director of the Center for Genetic and Cellular
Therapies at Duke. "It's a
pre-clinical study that shows the vaccine can work very
effectively in human
cells although it has yet to be proved effective in
humans," added the study's
senior investigator, Smita Nair. "The vaccine is
expected to be in tests for the
next several years."
Usually, cancer vaccines require large loads of tumor
from individual patients
from which researchers extract protein antigens, which
they then use to prime
that patient's immune system. Not all cancers express
the same antigens, so
this method requires analysis of the proteins each
patient's tumor expresses.
The Duke cancer vaccine skips that step because, by
inserting tumor RNA
directly into immune cells, the RNA can produce the
proteins specific to each
patient's cancer. Furthermore, unlike proteins, tumor
RNA can be amplified
many times over, so only a small amount of tumor is
needed from a patient.
Such a vaccine can be produced in an assembly line
fashion, and in fact, a
new cell processing laboratory at Duke is now gearing
up to produce mass
quantities of this vaccine. "While we need the RNA from
a patient, we do not
need to determine the antigen it expresses, or a
patient's immune fingerprint,
and we don't need a lot of tumor material," Nair said.
The center, under the leadership of surgeon Dr. H. Kim
Lyerly, will be making
vaccines for about 100 patients to be enrolled in the
second phase of a clinical
trial, testing the vaccine for breast, lung and
colorectal cancers. The first phase
of the trial has shown that the vaccine is not only
safe but can produce immune
responses in cancer patients.
Additionally, Lyerly has received federal Food and Drug
Administration
approval to start another phase 1 trial, using RNA
extracted from colon
cancer cells.
The Duke cancer vaccine harnesses two biological
powerhouses: the potency
of rare immune cells, called dendritic cells, whose job
it is seek out foreign
tissue and alert the immune system, and RNA, the agent
that transfers
information from a cell's genome to the protein
synthesis machinery of the cell.
Dendritic cells circulate throughout the body, looking
for "foreign" protein,
such as that produced by invading bacteria. The
dendritic cells then "eat" the
antigens, to display them on their own cell surface.
This show of a foreign
antigen signals a strong response from immune system
fighters known as "killer
T" cells which move out from the spleen and lymph nodes
to attack the
invader.
Cancer cells also produce a variety of atypical
proteins, Gilboa said, but
tumor cells have evolved ways of effectively hiding
these proteins from
surveying dendritic cells. In this way, cancer is
virtually invisible to the immune
system, which can only mount a very weak response at
best.
The Duke researchers have devised a way to engineer
dendritic cells to
display tumor antigens. Now they are testing whether
these cells will signal an
effective immune response. They reasoned that the best
way to get cancer
antigens into dendritic cells is to have those proteins
produced within the
dendritic cell itself. To do this they isolate and
remove RNA from tumor cells
and infuse it into dendritic cells. RNA thus
"transfected" into a host cell uses
that cell's machinery to make tumor proteins, which are
then chopped up and
displayed on the cell surface.
Mass quantities of the vaccine can be produced for each
patient using a
special cell processing laboratory. The vaccine is then
injected into the patient
to elicit an immune system against cancer in their
body.
Using a patient's own RNA to produce red-flag antigens
leaps a major hurdle
that has halted other attempts at devising an effective
and widely applicable
cancer vaccine, Gilboa said. It produces antigens that
are specific to that
individual's cancer. Many cancer immunotherapies may
fail because they rely
upon a single specific protein antigen that may or may
not be found in that
patient's tumor cells, Gilboa said. "It's difficult to
find a protein fragment that
works well for all patients, so the idea is to have a
patient's own RNA make
its cancer antigens."
In some vaccine trials, researchers have had to isolate
antigens directly from
tumors of cancer patients ? which is expensive and
problematic, Gilboa said.
This new strategy allows large quantities of vaccine to
be produced from a
small amount of tumor taken from a patient. Duke
researchers have the
technology to isolate dendritic cells from blood and
then grow mass quantities
of them.
The RNA from cancer cells also can be reproduced
millions of times using
current technology. The batch of RNA is then transfused
into the mass of
dendritic cells and injected into patients. "The
problem has been that most
cancer patients don't have enough tumor tissue in which
to isolate enough
antigen for vaccination," Gilboa said. "With this
method, we just need a small
quantity of cells."
To prove that the concept worked, the researchers
refined the vaccine several
times, as outlined in the study report. They tested the
vaccine using RNA that
coded for a specific antigen known as CEA
(carcinoembryonic antigen). CEA
is often expressed in breast, lung and colorectal
cancer. They mixed this RNA
sequence with dendritic cells and the CEA was produced
and displayed on
the dendritic cell. A strong immune response was seen
when this concoction
was exposed to the patient's cancer cells in a test
tube. This type of vaccine is
what is currently being tested in 18 patients, all of
whom expressed CEA
antigens.
The final test will be to see if "transfecting" the
entire RNA from tumor cells
into dendritic cells will produce a response, whether
or not the patient's cancer
expressed the CEA antigen. Their assumption is that the
RNA will produce
many antigens specific to that patient, and will induce
potent immune
responses that will eradicate the cancer. This vaccine,
when tested in animals
and in laboratory studies in a test tube was effective,
said center researcher
David Boczkowski, a contributing author. This is the
type of vaccine that will
be tested in the new clinical trial of colorectal
cancer patients
Other researchers contributing to the clinical study
included Dr. Michael
Morse and Dr. Yuping Deng.
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