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New Hope in Cancer Vaccines Emerges as Novel Therapies Are Developed and Tested

HOUSTON, Aug. 4 /PRNewswire/ -- 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. 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.

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


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


"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


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


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.


"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


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


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


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


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


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


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


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


"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.


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


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."


Learning to Turn the Human Immune System Against Cancer

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


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


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."

This news release was issued on behalf of Newswise. For more

information, visit http://www.newswise.com .

SOURCE The University of Texas M. D. Anderson Cancer Center

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