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Sept. 16, 2004
Vaccines show promise
Cancer Vaccines: Training the Immune System to Fight
Cancer
By Michelle Meadow,
FDA Consumer Magazine
Vaccines traditionally
have been used to prevent infectious diseases such as measles and the
flu. But with cancer vaccines, the emphasis is on treatment, at least
for now. The idea is to inject a preparation of inactivated cancer cells
or proteins that are unique to cancer cells into a person who has
cancer. The goal: to train the person's immune system to recognize the
living cancer cells and attack them. (See
"The Immune System and How It Works.")
"The best settings are
for treating people who have minimal disease or a high risk of
recurrence," says Jeffrey Schlom, Ph.D., chief of the Laboratory of
Tumor Immunology and Biology at the National Cancer Institute (NCI).
"But at this time, most therapeutic cancer vaccines are being studied in
people who have failed other therapies."
Cancer vaccines are
experimental; none have been licensed by the Food and Drug
Administration. But there are about a dozen cancer vaccines in advanced
clinical trials, says Steven Hirschfeld, M.D., a medical officer in the
FDA's Center for Biologics Evaluation and Research. "Research has shown
us that the fundamental approach to cancer vaccines is right; we are
moving in the right direction," he says.
The three standard
cancer therapies are surgery to remove tumors; chemotherapy, which
modifies or destroys cancer cells with drugs; and radiation, which
destroys cancer cells with high-energy X-rays. Immunotherapy, which
includes cancer vaccines, is considered a fourth, and still
investigational, type of therapy. Cancer vaccines are sometimes used
alone, but are often combined with a standard therapy.
While standard
treatments alone have proven effective, they also have limitations.
Radiation and chemotherapy can wipe out a person's cancer cells, but
they also damage normal cells. "We want to find treatment that is more
targeted and less toxic," says Hirschfeld. "Cancer vaccines are designed
to be specific, targeting only the cancer cells without harming the
healthy ones."
The approach has made
cancer vaccines generally well tolerated, allowing them to be used in
outpatient settings. And they can be added to standard therapy with a
low likelihood of causing further serious side effects.
How Cancer Vaccines Work
Cancer is a term for
more than 100 diseases characterized by the uncontrolled, abnormal
growth of cells. To the immune system--the body's natural defense system
against disease--cancer cells and normal cells look the same. The immune
system tends to tolerate the cancer cells, just as it tolerates the
normal cells. That's because the immune system doesn't recognize cancer
cells as something foreign, Hirschfeld says. Rather, cancer cells are
once-normal cells that have gone awry. Cancer vaccines try to get the
immune system to overcome its tolerance of cancer cells so that it can
recognize them and attack them.
All cells have unique
proteins or bits of proteins on their surface called antigens. Many
cancer cells make cancer-specific antigens. The goal of using cancer
antigens as a vaccine is to teach the immune system to recognize the
cancer-specific antigens and to reject any cells with those antigens.
The antigens activate white blood cells called B lymphocytes (B cells)
and T lymphocytes (T cells). B cells produce antibodies that recognize a
particular antigen and bind to it to help destroy the cancer cells. T
cells that recognize a particular antigen can attack and kill cancer
cells. In 1991, the first human cancer antigen was found in cells of a
person with melanoma, a discovery that encouraged researchers to search
for antigens on other types of cancer, according to the NCI.
The two main approaches
for cancer vaccines are whole-cell vaccines and antigen vaccines.
Whole-cell vaccines may take whole cancer cells from a patient or
sometimes several patients, or use human tumor cell lines derived in a
laboratory. "Some cell-based vaccines use tumor cells from the patient,
some contain something that looks like a tumor cell but was created in a
lab, and others are personalized vaccines that use some cells from the
patient and some from the lab," Hirschfeld says. Cells that are taken
from people with cancer are altered in a lab to inactivate them so that
they are safe to re-inject.
Regardless of the exact
source of the cells, whole cell vaccines potentially use all the
antigens found on the tumor cells. Antigen vaccines try to trigger an
immune response by using only certain antigens from cancer cells.
Hirschfeld says antigens may be particular to an individual, to a
certain type of cancer, or to several types of cancers.
Boosting the Immune
Response
In the early 1990s,
Steven Rosenberg, M.D., one of the pioneers of immunotherapy and chief
of surgery at the NCI, wrote that trying to use the immune system to
fight cancer is so difficult that it made him feel "like a dog trying to
bite a basketball." Among Rosenberg's contributions was identifying the
antigens that trigger an immune response, and cloning genes that look
for, or "code for," those antigens.
Researchers have been
working to develop cancer vaccines for more than 100 years in one form
or another, and the main mission has always been to make the immune
system's response to the cancer antigens as strong as possible.
One major strategy
involves combining vaccines with additional substances called adjuvants,
which act as chemical messengers that help T cells work better. An
example of one type of adjuvant, called a cytokine, is interleukin-2.
This protein is made by the body's immune system and can also be made in
a lab.
There have also been
improvements in vaccine delivery. For example, Schlom developed a
vaccine in which genes for tumor antigens are put into a weakened virus
called a "vector" that delivers genetic materials to cells. This makes
the tumor antigen more visible to the immune system. The CEA-TRICOM
vaccine was developed at the NCI through a cooperative research and
development agreement with Therion Biologics in Cambridge, Mass.
Researchers use the vaccinia virus, the same virus in the smallpox
vaccine, as the vector. The carcinoembryonic antigen (CEA), which is
found on most breast, lung, colon, and pancreatic tumors, is added to
the virus. Researchers also add three molecules, called "costimulatory
molecules," which serve as signals that make the vaccine more potent
than it would be if the antigen were used alone. A similar vaccine
developed under the NCI agreement with Therion is the PANVAC vaccine,
which has now entered advanced study as a treatment for pancreatic
cancer.
In addition to studying
this type of virus-based technique, researchers at Duke University's
Cancer Center in Durham, N.C., have been studying vaccines that mix
white blood cells called dendritic cells with genetic material from a
person's tumor.
Dendritic cells, which
can activate T cells, work by looking around, finding antigens, and
showing them to the fighter T cells. Researchers have found ways to
increase the number of dendritic cells in a vaccine. "Employing millions
of 'pumped up' dendritic cells can help elicit a strong immune
response," says H. Kim Lyerly, M.D., director of the Duke cancer center.
Recent work by Lyerly
and Duke investigators Michael Morse, M.D., and Timothy Clay, Ph.D., has
focused on modifying dendritic cells with viruses so that they activate
even stronger T cell responses against cancer antigens.
"This is an evolving
area, and it's exciting to be able to make progress," says Lyerly. "For
decades, people thought it wasn't even fundamentally possible to develop
cancer vaccines, and here we are. The science behind cancer vaccines is
leading us to believe that we will find the answers."
Promising, But Still
Early
As with any new
treatment, cancer vaccines must be first studied in lab animals and then
tested for safety and effectiveness in three phases of human studies,
called "clinical trials," before they can be approved by the FDA. In
Phase 1 clinical trials, cancer vaccines are used alone and studied for
safety and to determine the proper dose. In Phase 2 trials, they are
tested for effectiveness and may be used alone or in combination with
another therapy. Phase 3 trials are large-scale studies testing
effectiveness and usually comparing a vaccine with some standard
therapy. Researchers are testing vaccines using various adjuvants,
delivery methods, and types of antigens.
Cancer vaccines have
shown promise in clinical trials with many types of cancer. According to
Howard Streicher, M.D., a senior investigator with the NCI's Cancer
Therapy Evaluation Program, it's too soon to say which cancers will be
treated with vaccine therapy. The types of tumors that have proven most
susceptible to vaccines so far, he says, are: skin cancer (melanoma);
kidney cancer (renal cell); a group of cancers that affect the lymphatic
system (lymphoma); a malignant tumor of the bone marrow (myeloma); and
solid tumors, such as lung cancer. The most work has been done in the
area of melanoma, a type of skin cancer in which treatment options are
limited when the disease is in advanced stages.
"After having a tumor
removed, about half of patients with stage III melanoma may have a
recurrence, and we want to prevent that," Streicher says. "Chemotherapy
doesn't work in this area, so our hope is that this could be just the
right place for a vaccine."
James Mulé, M.D., Ph.D.,
associate director of the H. Lee Moffitt Cancer Center and Research
Institute in Tampa, Fla., says, though some early studies have shown
that some people's tumors shrank or even disappeared in response to a
cancer vaccine, it's still early. Mulé was an investigator on the first
study that tested dendritic cells in children. In the Phase 1 study, one
16-year-old with cancer that had spread to her lungs and spine showed
significant shrinkage of tumors.
"There is promise in the
sense that some of these vaccines can illicit a powerful immune response
in some patients, but I think we have to be careful about getting too
excited over early studies that can't be reproduced," Mulé says.
Jeffrey Weber, M.D.,
Ph.D., director of the Norris Melanoma Center at the University of
Southern California, says there is also still a lot of work to be done
in discovering new antigens and adjuvants and more sophisticated
strategies to overcome the immune system's tolerance of cancer cells.
"We are still discovering molecules that regulate the immune system such
as CTLA-4, so we're still in the dark in some areas," Weber says. Recent
research has found that inhibiting CTLA-4 can help the immune system
attack some tumors.
Experts say that no
therapeutic cancer vaccine has been licensed yet because few Phase 3
studies have been completed, and those that have been completed did not
meet their goals of demonstrating safety and effectiveness of the
vaccine. "We are still working with industry to define the
characteristics, including potency," says the FDA's Hirschfeld. "So a
trial may look promising early on, but our job is to make sure it can be
reproduced. We have to ask: 'Will this treatment work in the larger
population?'"
One of the challenges is
that cancer vaccines may produce different effects than those caused by
cancer drugs. With cancer drugs, experts ask whether there is an
objective, measurable response, such as tumor shrinkage. A cancer drug
may cause tumors to shrink, but a person still may not live longer. With
a cancer vaccine, there may be fewer signs of tumor shrinkage, but a
person might live longer.
There aren't the same
landmarks that you would see with traditional therapies, says Natalie
Sacks, M.D., medical director in the clinical research division at San
Francisco-based Cell Genesys, which is studying its vaccines, called
GVAX, in people with prostate cancer, pancreatic cancer, leukemia, and
myeloma. These whole-cell vaccines all use a hormone that stimulates
immune response, called granulocyte macrophage colony stimulating factor
(GM-CSF).
"As sponsors, we want to
develop treatments and get them out to the market and help patients,"
Sacks says. "In the case of cytotoxic chemotherapies, the traditional
endpoints used in drug development are shorter-term outcomes, such as
tumor response and progression-free survival. Where I expect
immunotherapy to be successful is in longer-term outcomes and increased
survival. Because of the mechanism of action, the patient may not show
an immediate response as is generally observed with standard
chemotherapies, and the trial may take longer."
Finding a Clinical Trial
Cancer researchers say
their work won't mean much if more people don't enroll in clinical
trials. According to the NCI, less than 3 percent of U.S. adults with
cancer participate in clinical trials.
If there is a standard
treatment available for a type of cancer, the NCI recommends choosing it
over an experimental therapy. Cancer vaccines show the most promise at
preventing a recurrence of cancer after surgery, radiation, or
chemotherapy because the immune system will need to recognize and attack
a smaller number of cancer cells. Cancer vaccines are also being tested
as a treatment for advanced cancer.
Gary Montgomery, 66, of
Redmond, Wash., enrolled in a cancer vaccine trial in 2002 to treat a
rare form of abdominal cancer called pseudomyxoma peritonei. According
to the National Organization for Rare Disorders, the disease is
characterized by the accumulation of mucus-secreting tumor cells in the
abdomen and pelvis. As the mass of tumor cells grows, the abdomen swells
and digestive function becomes impaired.
Montgomery first had the
standard therapy of surgery to remove the tumors in 2000. "They opened
me up like a sardine can--from the sternum to the abdomen--and took out
as many tumors as possible," Montgomery says. Then they inserted a tube
into the abdomen, which delivered chemotherapy for six months. He
experienced no tumor growth for about a year, but then the tumors came
back. "It's known as a relentless form of cancer that wears you down,"
he says. "The doctor said that with the exception of another surgery,
there was really nothing else they could do."
So Montgomery started
with the Internet and found one NCI study that involved surgery and
chemotherapy with an agent different from the one he had before. But the
trial was closed. Taking advice from a friend, he checked at the
Lombardi Cancer Center at Georgetown University in Washington, D.C. "I
was feeling pretty low at this point," he says. He found out the one
vaccine study he was interested in had just ended. But a nurse told him
that another trial with newer versions of cancer vaccines developed at
the NCI was about to start. "There were two slots left," he says.
"Luckily, I met the criteria."
Montgomery received a
"prime-boost regimen" of Therion Biologics' TRICOM vaccine. He first
received an injection in the upper leg of a modified version of the
smallpox vaccine to prime the immune system. Then he received monthly
boosters of a vaccine called fowlpox CEA (carcinoembryonic antigen), an
antigen found on most colorectal and pancreatic cancers. He also
received a shot of the hormone GM-CSF, which helps stimulate the cells
of the immune system. He had to give some of the injections to himself
when he arrived back home in Washington state.
He says he experienced
minimal side effects, such as soreness at the site of injection and mild
flu-like symptoms. Though most cancer vaccines have been well-tolerated,
in other trials some people have experienced autoimmune problems such as
inflammation of the thyroid gland, skin disorders, and colitis.
Autoimmune conditions are those in which the immune system mistakenly
attacks the body's tissues and organs. Before he began the trial,
Montgomery signed an informed consent form acknowledging that he was
aware of all the risks.
Montgomery continues to
participate in the trial and flies to the nation's capital every month
to receive treatment because it's been working. "It hasn't cured the
cancer," Montgomery says, "but it seems to be keeping it in check. And
that's good enough for me."
Those interested in
finding out about clinical trials to treat cancer should talk with their
doctors and contact the NCI at (800) 4-CANCER (422-6237) or on the Web
at
www.clinicaltrials.gov.
The Immune System and
How It Works
Your immune system
includes your spleen, lymph nodes, tonsils, bone marrow, and white blood
cells. These all help protect you from getting infections and diseases.
When your immune system works the way it should, it can tell the
difference between "good" cells that keep you healthy and "bad" cells
that make you sick. But sometimes this doesn't happen. Doctors are doing
research to learn why some immune systems don't fight off diseases like
cancer.
White blood cells are an
important part of your immune system. When your doctor or nurse talks
about your white blood cells, he or she may use words like:
Monocytes
(MON-o-cites) are types of white blood cells.
Lymphocytes
(LYM-fo-cites) are types of white blood cells.
B
cells, T cells,
and "natural killer cells" are kinds of lymphocytes.
Cancer Vaccine Facts
Cancer vaccines are intended either to treat existing cancers
(therapeutic vaccines) or to prevent the development of cancer
(prophylactic vaccines).
Therapeutic vaccines, which are administered to cancer patients, are
designed to treat cancer by stimulating the immune system to recognize
and attack human cancer cells without harming normal cells. Prophylactic
vaccines, on the other hand, are given to healthy individuals to
stimulate the immune system to attack cancer-causing viruses and prevent
viral infection.
The
only cancer vaccine licensed by the Food and Drug Administration is a
prophylactic vaccine against hepatitis B virus, an infectious agent
associated with liver cancer.
Scientists are currently evaluating several different vaccines in large
human trials to determine which approaches are most effective for
particular kinds of cancers.
Source: National
Cancer Institute
The Role of FDA and NCI
After conducting
preclinical research in lab animals, drug companies or clinical
investigators submit an investigational new drug application to the Food
and Drug Administration, requesting permission to move forward with
testing in humans called clinical trials. The agency and the sponsors
continue to communicate throughout the three phases of clinical trials,
and the FDA ensures that treatments are safe and effective before they
can be marketed.
The National Cancer
Institute (NCI) is the main federal agency that supports and conducts
cancer research. The NCI funds studies conducted by hospitals,
universities, and businesses. The institute also supports a network of
cancer centers across the country.
Both agencies are part
of the U.S. Department of Health and Human Services, and they share
responsibility and oversight for clinical trials. In 2003, the FDA and
the NCI entered an agreement to enhance the efficiency of clinical
research and the evaluation of new cancer medications. An NCI-FDA
Oncology Task Force involves senior staff from both agencies and
oversees the agreement. The agencies collaborate on developing the
markers that show whether a treatment is effective, such as survival
time, tumor shrinkage, and time to relapse.
New Cancer Office and
Program
In July 2004 the FDA
announced plans to create the Office of Oncology Drug Products, which
will be housed in the agency's Center for Drug Evaluation and Research (CDER).
The new office will consolidate three existing areas within CDER that
are responsible for reviewing drugs and biologics used to prevent,
diagnose, and treat cancer. The creation of this office will improve the
consistency of review and policy toward oncology drugs and bring
together oncologists who will help develop new therapies.
"Biomedical research in
the United States is second to none, and it is our responsibility to see
that patients reap the fruits of that research," says Health and Human
Services Secretary Tommy G. Thompson. "We are committed to creating the
most effective and efficient review process possible to ensure
life-saving treatments are made available to cancer patients."
The FDA also is creating
a new oncology program within the office, which will coordinate
cancer-related work performed throughout the FDA. The program will
promote cross-agency consultation and discussion and the development of
regulatory policy and standards, and will serve as a focal point for
agency interactions with the National Cancer Institute and other
stakeholders.
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