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Senior Citizen Health & Medicine
New Hope in Cancer Vaccines Emerges as Novel
Therapies Develop
M.D. Anderson scientists say advances in immunology
help in vaccine design
 August 4, 2006 - Medicine can now prevent a host of
diseases with a mere shot of vaccine. Polio and smallpox are almost
non-existent, and mumps and chicken pox are rarely seen nowadays. Senior
citizens cheered in May when the FDA
approved Zostavax, a new vaccine to reduce the risk of shingles.
And for the first time, the prospect of eradicating a specific cancer
through vaccination is possible. The newly approved human papillomavirus
(HPV) vaccine is designed to curb the 230,000 worldwide deaths due to
cervical cancer, which is caused solely by HPV. And the hepatitis B
virus, responsible for 70 percent of all liver cancer deaths, is also
preventable with a vaccine.
Cancer researchers are working on the next era of
vaccines designed to treat cancer that has already developed. These
vaccines don't rev up the human immune system to attack an invading
microbe, but prime the system to go after a unique biological tag found
only on tumor cells.
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Zostavax Shingles Vaccine
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May 26, 2006 - The Food
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Health & Medicine |
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For example, brain cancer researchers at The
University of Texas M. D. Anderson Cancer Center are testing an
experimental vaccine that homes to a protein studding the surface of
glioblastoma cancer cells. It tricks the body into thinking this protein
is foreign and infectious, which alerts killer immune cells. The same
kind of strategy is producing very promising results in clinical trials
at M. D. Anderson of vaccines for advanced myeloid leukemia as well as
other forms of leukemia, aggressive lymphoma and melanoma.
Because of the preliminary nature of therapeutic
cancer vaccines - none has yet been approved for use anywhere in the
world - researchers can only describe their findings as "promising." But
their hope in the therapy is clear. In fact, several M. D. Anderson
vaccine clinical trials have shown strong anti-tumor activity and one
produced the first clinical demonstration that a vaccine could produce
complete molecular remission - meaning, no biological evidence of cancer
remained in some treated patients.
This wealth of cancer vaccine research at M. D.
Anderson - possibly the most varied and advanced in the nation - has
come about because of the strong interest from M. D. Anderson physicians
and researchers in basic immunological science. They believe that the
human immune system can be used against cancer, and that vaccines may
represent the cutting edge of immunologic cancer treatment.
"Hypothetically, once the immune system has been
sufficiently stimulated, it would be able to find and destroy every
single tumor cell throughout the body," says Yong-Jun Liu, M.D., Ph.D.,
chair of the Department of Immunology and director of the Center for
Cancer Immunology Research (CCIR).
"It could do this without destroying healthy
tissue," he says. "That's the goal we strive every day for." Liu and
other CCIR researchers believe that, ultimately, the best use of such
vaccines will be to eliminate the minimal disease that remains after
initial cancer therapy.
"When there is too much disease, the immune system
is overwhelmed and a cancer vaccine may not be helpful," says Jorge
Cortes, M.D., a professor in the Department of Leukemia. "But after
patients have been treated, there is often a low level of disease, so
our idea is that we can add a vaccine at that point to eliminate the
cancer before it has a chance to grow back again."
"This is an exciting time in cancer research, given
our increased understanding of the molecular nature of cancer and the
immune response," says Patrick Hwu, M.D., chair of the Department of
Melanoma. "Our ultimate success will likely depend on the rational
combination of appropriate chemotherapies, targeted therapies, and
immunotherapy, such as therapeutic cancer vaccines."
Starting with leukemia antigen
All of the cancer vaccine tactics being developed and tested at M. D.
Anderson aim to mislead the cancer patient's immune system into thinking
it is attacking bacteria or a virus (see sidebar). They are designed to
strengthen the body's natural defenses against a cancer that has already
developed, and this could stop an existing tumor from growing further,
prevent cancer from coming back after it has been treated, or eliminate
cancer cells not killed by previous treatments.
These efforts are concentrated on a subset of
cancers that M. D. Anderson researchers believe are most amenable to
cancer vaccines - the leukemia and lymphoma blood-based cancers (because
red and white blood and lymph system cells are easier to reach and
manipulate) and a few solid tumors, including melanoma, which seem to
elicit a natural, if weak, immune response.
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by Leroy Sievers
"Wait
for the cavalry. They should be here any minute. Or month.
Or year. That's sort of the advice that many cancer patients are
given..."
After that day, your life is
never the same. "That day" is the day the doctor
tells you, "You have cancer." Every one of us
knows someone who's had to face that news. It's
scary, it's sad. But it's still life, and it's a
life worth living. "My Cancer" is a daily
account of my life and my fight with cancer.
Read more at NPR...
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In 2003, recognizing this focus, M. D. Anderson
opened its Center for Cancer Immunology Research, which is believed to
be the first comprehensive program in the United States in which both
basic and clinical immunologists work together in open laboratory
environments to develop immunological treatments for cancer.
The four M. D. Anderson departments that
collaborate within the Center for Cancer Immunology Research -
Immunology, Lymphoma and Myeloma, Melanoma, and Blood and Marrow
Transplantation - have built up strong basic and translational research
programs to develop novel vaccines, manufacture them in on-site cell
processing facilities, and test them in patients.
Among the scientists who are leading this effort
are Larry Kwak, M.D., Ph.D., chair of the Department of Lymphoma, and
Patrick Hwu, the Department of Melanoma chair, both of whom were
recently recruited from the National Institutes of Health (NIH). They
join Liu, a leading immunologist who came to M. D. Anderson in 2002 from
the biotech and pharmaceutical industry, and Jeffrey Molldrem, M.D.,
professor in the Department of Blood & Marrow Transplantation, who
helped pioneer cancer vaccine research at M. D. Anderson.
"We have a number of homegrown vaccines, pioneered
in research laboratories at M. D. Anderson, that are true examples of
translational research," Kwak says. "The Center for Cancer Immunology
Research exists in part to take promising therapeutic agents from our
own institutional pipeline into patient care, and this strategy is
thriving."
Molldrem's vaccine, developed about 10 years ago to
treat advanced myeloid leukemia, demonstrated success from the
beginning, and now is being tested across M. D. Anderson in different
types of leukemia that originate from myeloid blood cells.
Molldrem and his team were able to find that a
special tumor antigen, which they called PR1, is over-expressed in
myeloid leukemia cells. The vaccine combines PR1 with a substance that
stimulates the immune system and directs T cells to kill the leukemia
and leave normal cells alone. The first test of the peptide vaccine
demonstrated that it could produce complete responses in some patients
with advanced myeloid leukemia for whom no other therapy had been
successful.
Such early success "startled" Molldrem, he says.
"Initially, we were just trying to see if we could boost immunity to the
antigen we had identified - we didn't expect molecular remissions,
especially in a phase I trial and in such a refractory group. That's
never been described before for any vaccine," he says.
Further testing has shown that the vaccine can
induce complete responses in 20 percent of patients with advanced acute
leukemia for whom all forms of chemotherapy had failed. Furthermore, the
vaccine also appears to offer an immune memory after only three doses,
says Muzaffar Qazilbash, M.D., an assistant professor in the Department
of Blood and Marrow Transplantation who is leading an ongoing clinical
trial.
The PR1 peptide vaccine is slated to be tested at
M. D. Anderson in other kinds of leukemia of myeloid origin, such as
acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML),
and pre-leukemic myelodysplastic syndromes.
A vaccine can even be useful in patients who
respond well to treatment, says Cortes, because even the best therapies
may not eliminate all traces of disease. For example, Cortes is testing
the PR1 peptide vaccine in CML patients who have done well with Gleevec
therapy, which keeps the cancer at bay when continuously used, but does
not eliminate it. "Even with the great drugs that we now have to treat
CML, we get to the point where the last bit of disease stubbornly
remains, and we may need something else to keep it under control or
eliminate it," Cortes says. "There is some evidence that an immune
response can play a role in eliminating these cancers, so using a
vaccine is a great idea."
Cortes has just opened a clinical trial testing the
concept in CML patients who will continue to be treated with Gleevec.
Twenty patients will receive the vaccine and another 20 will receive a
combination of the vaccine and interferon, which stimulates an immune
response. "Gleevec was the first major breakthrough in CML treatment,
and, in my opinion, the next one will be immune modulation," Cortes
says.
 Testing personalized vaccines
Early vaccine research in lymphoma (a cancer of lymphocytic white blood
cells) dates back to studies in mice in the 1970s when a lymphoma tumor
antigen was found. That discovery led Kwak, then at the National Cancer
Institute (NCI), to test a highly promising lymphoma therapeutic
vaccine. First reports of its success, in 1999, demonstrated complete
molecular remissions and long-term disease-free survival in 75 percent
of patients who used the vaccine after chemotherapy for lymphoma.
The vaccine, now known as Biovaxid after being
licensed to a biotech firm by NCI, is now being tested in a national
phase III clinical trial. This study, led at M. D. Anderson by Sattva
Neelapu, M.D., assistant professor of lymphoma, is testing the therapy
in 460 patients with follicular lymphoma, a form of non-Hodgkin
lymphoma.
The difference between this vaccine and the PR1
peptide vaccine is that it is an "idiotype" vaccine, tailored to the
patient's unique tumor antigens, says Kwak, who has continued his
vaccine studies at M. D. Anderson. In this individualized therapy, cells
are harvested from a patient's lymph node, and the unique cancer markers
on the outside of their cancer cells are identified. To create the
idiotype vaccine, researchers fuse the antigen-bearing tumor cells to
antibody-producing mouse cells that act as mini-factories, churning out
large quantities of the protein antigens, which are then given back to
patients with an immune system booster.
In a bid to see if a more "robust" cancer vaccine
can be produced, Neelapu, who was part of Kwak's team at the NCI, has
opened two trials at M. D. Anderson in which healthy volunteers are
vaccinated. These trials, in which Sergio Giralt, M.D., a professor in
the Department of Blood and Marrow Transplantation, is collaborating,
are for treatment of patients with multiple myeloma who are slated to
receive a stem cell transplant from a matched donor.
In this strategy, which will also be tested in
patients at the NIH, stem cell donors will be vaccinated with the
patient's tumor antigen. "The donor has a healthy immune system and can
mount a reaction against the antigen," says Neelapu. Those primed stem
cells will then be given back to the patient, "improving the chance of a
graf-versus-myeloma effect," he says.
Also being tested at M. D. Anderson are two
different idiotype vaccines to treat chronic lymphocytic leukemia (CLL),
a cancer in which the bone marrow makes too many lymphocytes.
One of the vaccines, co-developed by William
Wierda, M.D., Ph.D., assistant professor in the Department of Leukemia,
with collaborators at the University of California, San Diego, uses gene
therapy techniques. Tumor blood cells are extracted from patients, and
then sent to a cell processing facility at M. D. Anderson, where the
cells are infected with a virus that carries a gene that activates the
immune system. When the cells are given back to the patients, the
transformed leukemia cells manufacture the activation protein and
thereby function as a vaccine, says Wierda. "Leukemia cells efficiently
stimulate T cells to react against them as well as against nearby
leukemia cells that haven't been infected by the virus," he says. The
clinical trial is enrolling patients and will test whether a single dose
of the vaccine can produce an immune reaction against the leukemia.
The second vaccine, known as MyVax and developed by
Genitope Corporation, is now being tested in a phase I/II trial at nine
institutions. It combines an idiotype antigen from individual patient's
tumor cells with an immune stimulant derived from shellfish. "Because
this trial is in the early stages, the intent is to see if the vaccine
stimulates an immune response to the point that chemotherapy treatment
can be delayed in these patients," says Wierda, who is leading the trial
at M. D. Anderson.
"The chemotherapies that we have now for CLL are
very successful in putting patients into remission, but the majority
will relapse," says Wierda. "If we are able to stimulate an immune
reaction against leukemia cells while there is minimal disease, it could
offer us a curative strategy."
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Learning to Turn the Human Immune System Against
Cancer
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 It is significantly more challenging to develop
vaccines against cancer than against bacteria and viruses, says M. D.
Anderson's Patrick Hwu, M.D., chair of the Department of Melanoma.
Preventing infection with a vaccine is relatively
straightforward, he says, because it capitalizes on the body's elegant
immune system, which is primarily set up to recognize and attack foreign
proteins ("antigens") found on invading microbes. "We live in a sea of
bacteria and viruses, and our immune system has evolved to recognize the
biology of these pathogens in order to mount potent responses against
them," he says.
So a traditional vaccine introduces a
non-infectious "bit" of the pathogen antigen to a body that has not been
infected by it before, and this brief and harmless exposure activates
the immune system against the microbe and sets up a long term memory
that confers lasting protection.
But cancers are "derived from our own tissues, and
therefore our patrolling immune system is not programmed to recognize
cancer cells as foreign," says Hwu.
"The immune system is not very willing to attack
things that look like itself or the host, and there are all kinds of
regulatory circuits that keep the immune system down if everything
appears to be normal, even though it might not be," says Willem
Overwijk, Ph.D., a translational scientist who works on melanoma
vaccines.
That may be because "cancer does not really
threaten the existence of the human species, as do infectious diseases,
because most cancers occur after age 65," speculates Yong-Jun Liu, M.D.,
Ph.D., head of M. D. Anderson's Center for Cancer Immunology Research
and chair of the Department of Immunology.
However, Liu adds, the existence of autoimmune
disease indicates that the immune system is capable of attacking "self"
tissue. "The trick is learning how to get it to attack malignant tissue
instead," he says.
Another major problem is that viruses and bacteria
cause a lot of damage to tissue, which produces inflammation - another
red flag that stokes the immune system to act. An effective vaccine
might have to do the same, researchers say.
The challenge, then, is to "create" a lasting
immune response through a vaccine. While past decades of effort in this
direction have only produced tepid results, experts now believe they
know enough about human immunity to design rational approaches.
"Cancer vaccine strategies have a long history in
medicine and that history hasn't been very favorable," says M. D.
Anderson leukemia physician and researcher William Wierda, M.D. "We've
gone through periods of excitement and disappointment, and now we are in
a period of excitement again."
One reason, he says, is that the research community
has been able to find pieces of protein antigens either on the outside
or the inside of tumors that are relatively unique to cancer cells. The
job now is to manipulate the immune system's dendritic sentinel cells
and the destroying T cells to hunt them down and destroy them in the
same way that those cells attack microbes.
"A fundamental understanding of the immune system
has only been developed over the last four decades or so, and that
knowledge is critical for developing cancer vaccines," says Jeffrey
Molldrem, M.D., professor in the Department of Blood & Marrow
Transplantation.
"For instance, one of the trickiest parts is to
identify which antigens to direct the immune response against any given
tumor type," he says. "There can be tens of thousands of different
proteins and protein variants getting turned over at different times in
a cell, so trying to identify which ones the T cell actually sees is
kind of like finding a needle in a haystack," Molldrem says. "But now we
have a molecular scale for understanding how it works, which is an
important tool for directing immune reactions against a tumor."
Investigators at M. D. Anderson now have a toolbox
of protein antigens that they can use to create vaccines. The idea is to
take specific antigens that are over-expressed on certain tumor cells
and manipulate them to stimulate the body's T cells to destroy all
cancer cells expressing that antigen, says Hwu. Another strategy is to
grow T cells which recognize the tumor, then administer them back to the
patient to destroy the cancer cells.
Scientists are also working to imprint each newly
primed cell with a long-lasting memory that will enable it to fight
cancers as they develop, again in the same way that polio and measles
vaccines work over time, Liu says. Patients can then be immunized
against cancer recurrence or even against cancer development.
"We are applying principles learned from the
natural immune response to pathogens in the generation of new anti-tumor
vaccines," Hwu says. "As cancer researchers, our goal is to harness the
power of the immune system against cancer."
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Expanding melanoma's immune army
Melanoma is one of the few solid tumors that the human immune system
seems to "see," says Hwu, the Department of Melanoma chair. But that
natural T cell response to an antigen on the melanoma cell is too weak
to conquer a growing tumor, so researchers led by Hwu have found ways to
isolate T cells from patients' tumors, grow them in large quantities in
the lab and give them back to patients. This strategy, known as
"adoptive T-cell transfer," differs from that taken by Kwak, because Hwu
is providing more immune system "ammunition" to attack the already
existing tumor antigens.
Before coming to M. D. Anderson from the NCI in
2003, Hwu found this method could shrink tumors in about half of
patients with metastatic melanoma - a higher response rate than any
other therapy for this advanced cancer.
His challenge, however, has been to come up with
ways to grow the T cells efficiently, Hwu says. "We are trying to
develop a way to make this process easier and more effective."
Hwu has begun testing what he hopes is an improved
version of this approach. It involves isolating a patient's dendritic
cells (immune cells that first detect microbes and alert T cell killers)
and infusing them with billions of T cells that have been isolated from
patients and expanded in the laboratory. Before patients receive
chemotherapy to treat their melanoma, investigators take a blood sample
to isolate the dendritic cells, which are then grown in the laboratory
and exposed to the patient's melanoma antigen, says Willem Overwijk,
Ph.D., an assistant professor in the Department of Melanoma Medical
Oncology. "The dendritic cells take up the antigen and are ready to
present it to T cells, which will cause the T cells to become
activated," says Overwijk, who helped develop this approach.
A clinical trial testing this protocol opened in
early 2006, after Hwu and his research team worked for two years with
the NIH and the U.S. Food and Drug Administration on the protocol. In
this phase I/II study, 50 patients will all receive a short course of
chemotherapy while their cells are being grown in the lab. Half then
will receive an expanded mixture of their own dendritic and T cells,
while the other half will receive only T cells.
"This novel trial is so incredibly complicated and
involved that few places can do it," says Overwijk. "M. D. Anderson has
the infrastructure and the expertise to make it possible to do all this
in house. It may take this kind of effort to make an impact in treatment
of melanoma."
While adoptive T cell transfer may be required for
advanced melanoma, earlier stage diseases may be treated with vaccines
alone. In another trial for patients with early stage melanoma, Hwu and
his team are combining a vaccine to stimulate T cells with the prostate
cancer drug Lupron, which obstructs production of testosterone. It turns
out, says Hwu, that when sex hormones are blocked, the thymus gland
begins to produce new T cells. This is a "wonderful surprise," says Hwu,
because the thymus gland largely shuts down T cell production after
puberty. "The drug will produce a working thymus, which will be primed
by the T cell vaccine," he says.
Glioblastoma
Another solid tumor - one that is even more treacherous than melanoma -
appears to respond to a novel vaccine being developed and tested at M.
D. Anderson.
This vaccine significantly increased life
expectancy in patients with glioblastoma multiforme (GBM), the most
dangerous type of brain tumor. The results were so surprising that the
trial was stopped before full accrual, and a pharmaceutical company
acquired the rights to the drug. A larger, multi-institutional,
randomized study is being planned, says Amy Heimberger, M.D., an
assistant professor of Neurosurgery who led the trial, conducted at both
M. D. Anderson and at Duke University Medical Center.
She describes the vaccine as an easy to use
"off-the-shelf" treatment that can potentially help up to 50 percent of
all GBM patients keep their cancer at bay for a period of time. Interim
results of the Phase II clinical trial show that the vaccine
significantly delays progression of tumors until the cancer finds a new
growth pathway.
According to results Heimberger presented in April
at the annual meeting of the American Association of Neurological
Surgeons (AANS), median survival for the 23 patients tested is at least
19 months, and only four patients have died from the cancer, That figure
surpasses the median survival of 14 months for patients with GBM who are
treated with the most current chemotherapy and radiation, and the
4-month median survival for untreated patients, she says.
"We can't say this vaccine is better than
chemotherapy because we haven't tested the two treatments head-to-head
yet," she says. "However, so far, results have exceeded the expectations
we had for this vaccine."
Heimberger and a team of researchers designed the
vaccine to alert the brain's immune system to the presence of just one
type of protein that studs the outside of a glioma tumor. This protein,
epidermal growth factor variant III (EGFRvIII), is found on 30 percent
to 50 percent of brain tumors, as well as on some breast and
non-small-cell lung cancers, but not on normal tissue. Heimberger
believes EGFRvIII drives gliomas to spread, which could explain why
these brain tumors are unusually dangerous and invasive.
The vaccine contains a synthesized piece of the
EGFRvIII antigen, as well as compounds that stimulate immune system
dendritic cells, which then activate the immune system in general and
killer T cells in particular. "It tricks the body into thinking that
EGFRvIII is foreign, and the T cells are sent in to kill the tumor,"
Heimberger says.
"This is a proof of concept, and optimal use of the
vaccine may be with chemotherapy to further retard progression," says
Heimberger. "Still, this is exciting to us because people have been
trying to use immunotherapy against gliomas for a long time."
>> Source:
University of Texas M. D. Anderson Cancer Center
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