As reported by The Chronicle of Higher Education, November 12, 2004.

Teaching the Body to Kill Cancer

Researchers work on vaccines to fend off tumors

By Lila Guterman

The human immune system is acutely sensitive to the body's enemies. Unperturbed by native cells, immune fighters roar into action when viruses or other foreigners infiltrate the body.

Unfortunately for many people, the immune system has difficulty telling friend from foe when confronted with cancer. Tumor cells so closely resemble normal cells that they often go undetected by the body's defenses.

But more and more researchers think that, with prodding from a vaccine, the immune system could learn to fight off tumors lurking in the body. Several scientists described their research on vaccines at an international conference held last month in New York by the Cancer Research Institute, a nonprofit organization that finances work on cancer immunology. Early results from clinical trials have been tantalizing. After experimental treatments, a few patients' immune systems have mounted an effective defense against otherwise deadly cancers, although the treatments do not work for many people.

Such therapies are not traditional vaccines, like the polio vaccine, which are given in the absence of disease and train the immune system to ward off an illness it has not yet encountered. The proposed vaccines would be given to patients who already have cancer. They would teach the immune system to beat back tumors, or at least stop them from spreading and growing ever larger.

"One could not say this five years ago," says Pramod K. Srivastava, a professor of immunology at the University of Connecticut School of Medicine, "but today I think one could say that in the next two to five years, we'll see some of these things being prescribed for treatment."

'Self' and 'Non-Self'

The immune system is exquisite in its complexity, with antibodies and cells receiving and sending signals to destroy intruders. Thanks to antigens, protein fragments that all cells display on their surfaces, a healthy person's immune system can tell the difference between "self" (cells in the skin, pancreas, and lungs, for example) and "non-self" (viruses and bacteria).

In recent years immunologists have made great progress in discovering antigens that tumors wear on their surfaces. Many of the tumor antigens match those on healthy cells, but a few are unique to tumors. If a vaccine could teach the immune system to recognize those cancer antigens, the body itself might destroy the tumor. What's more, unlike chemotherapy and radiation, a vaccine-boosted immune system should leave healthy tissues alone.

Many researchers are trying to use tumor antigens as vaccines, along with compounds that help wake the immune system. If immune cells are primed to recognize the antigens from the vaccine, they should also recognize those antigens on a tumor cell, and proceed to destroy it.

One of the scientists at last month's conference, Kunle Odunsi, an assistant professor of obstetrics and gynecology at the Roswell Park Cancer Institute, in Buffalo, N.Y., is trying an antigen-based vaccine to treat patients with ovarian cancer -- a disease in which most patients' tumors get smaller with chemotherapy, but ultimately the patients have a relapse and become incurable.

He is testing a vaccine containing a protein fragment called NY-ESO-1 on 18 patients whose tumors bear that antigen (not all patients' tumors do). The patients had already undergone chemotherapy, and 11 of them had no signs of cancer when they received the experimental treatment, between June 2003 and this August.

The experiment is a phase-one trial, which means it is designed to test the toxicity of the vaccine rather than its effectiveness. But Dr. Odunsi reported at the conference that those 11 patients are still free of disease, suggesting that the vaccine may be helping them ward off the cancer's return. Ovarian-cancer patients typically suffer a relapse after a year or more, he says. Unfortunately, the seven patients who had some remaining cancer when the clinical trial began did not do as well; in fact, one has died from the disease.

Other researchers using similar approaches have also had mixed results. Some scientists therefore think that the key to more-effective cancer vaccines might be to employ compounds other than the antigens as the therapy's main component.

Mr. Srivastava, for instance, envelops the antigens in a larger biomolecule called a heat-shock protein, which, he suggests, more effectively signals their presence to the immune system. In effect, the heat-shock protein prompts the antigens to shout to the immune system to wake up, while the antigens on their own only whisper.

Mr. Srivastava's experimental vaccine is trickier to make than one using the antigens alone because it is a personalized vaccine. A biotechnology company that he formed, Antigenics Inc., creates experimental vaccines by using heat-shock proteins (and their associated antigens), which are extracted from each patient's tumor tissue after it has been removed surgically.

Antigenics has already tested the vaccine on hundreds of patients in several small and medium-size clinical trials designed to find a dose that can be given safely. The experiments hinted that the vaccine could prevent tumors from growing in some cancer patients. But only large trials can prove whether a new therapy is effective.

The first large-scale trial of the heat-shock-protein vaccine is winding down; Mr. Srivastava says he should know in about six months whether the vaccine can prevent recurrence of kidney cancer. Around 700 patients were enrolled in the trial; half received surgery alone (the normal procedure in treating kidney cancer), and the other half received the vaccine after surgery. Another major trial, of 300 patients with melanoma, is also taking place.

Custom Vaccines

Some scientists express concern about the difficulty and cost of making personalized vaccines. But Mr. Srivastava said at the conference that Antigenics has been able to produce vaccines for 95 percent of patients. "If you can make a vaccine that works," he says in an interview, "the market will bear the cost."

Personalizing vaccines is a strategy that Ronald Levy has espoused for years, but for a very different type of cancer. Dr. Levy, a professor and chief of the division of oncology at the Stanford University School of Medicine, studies cancers of the immune system itself.

Each lymphocyte, a type of white blood cell that is key to the immune response, bears a unique external receptor that recognizes just one antigen. In patients with lymphoma, one of those lymphocytes grows uncontrollably, creating a tumor. All the cells of the tumor bear the same receptor.

The receptor has become Dr. Levy's experimental vaccine for patients with non-Hodgkin's lymphoma, which is incurable and is the sixth-most-common cancer in the United States. Each patient in his experiments receives an injection of 1017 -- one-hundred-thousand trillion -- copies of his or her own tumor receptor, coupled to another protein that is known to arouse the immune system. He has found that about half of the patients who receive the vaccine mount immune responses that recognize the tumor as foreign.

Those results were good enough to spur Genitope Corporation, a biotechnology company that is trying to develop the vaccine for market, to do a large-scale human trial. About 700 people will receive the vaccine after undergoing chemotherapy to shrink their cancers. Dr. Levy and the other scientists performing the trial hope that the vaccine will slow the cancer's reappearance.

Making a new vaccine for each person is, he admits, "daunting." The process takes a few months. Dr. Levy sees the treatment as akin to providing a service, not just selling a commodity. "It's not the usual business of drug companies," he says.

Unleashing the Immune System

Most companies prefer a one-size-fits-all strategy. James P. Allison, chairman of the immunology program at Memorial Sloan-Kettering Cancer Center, in New York, thinks he has found one. He has discovered that a naturally occurring molecule called CTLA-4 damps down the immune response to invaders. Tie up CTLA-4 with a blocker molecule, he reasoned, and the immune system should provide a stronger defense against many cancers.

He has tested the strategy using molecules that disable CTLA-4. After treatment with the blocker, mice with tumors not only destroyed their cancers but also could fight off recurrences. "It worked spectacularly," he says.

Since some types of cancer nonetheless remained invisible to the immune system, however, Mr. Allison's team tried combining the blocker molecule with other vaccines and found that their effect was synergistic.

But the major test remained: Would it work for human beings? So far, the answer -- as with so many other promising experimental vaccines -- seems to be that it works for some people. A company called Medarex, which is working to bring a CTLA-4 blocker to market, has done or is planning some 20 human trials, according to Israel Lowy, director of clinical science and infectious diseases. In one small trial, Mr. Allison's therapy was tested in combination with an antigen-based vaccine in people with melanoma. In about 20 percent of patients, tumors shrank by at least half. A few patients went into complete remission.

"The most exciting thing about that is how durable these responses are," says Mr. Allison. "A lot of drugs give three months or six months [of remission], and people get excited about it." With this treatment, two years after the trial, some patients' cancers have not returned.

Medarex is beginning a large-scale human trial in the treatment of melanoma. If all goes well, says Mr. Allison, the CTLA-4 blocker could be on the market in a few years.

The drug has only minor side effects, unless it is given repeatedly over a short period. Then people's immune system can attack healthy tissues, causing side effects like severe gastrointestinal problems, although they can be treated with other medicines. When patients weigh the unpleasant side effects against disappearing tumors, says Dr. Lowy, "it's been well worth it."

Vaccine Concerns

Still, the combination of vaccine and the CTLA-4 blocker seems to work for only a fraction of patients, causing one medical authority to question the overall vaccine strategy. "Cancer-vaccine approaches have not been clinically effective," says Steven A. Rosenberg, chief of surgery at the National Cancer Institute, who has done more research on cancer vaccines than perhaps any other scientist.

Although he is still working on vaccines -- and, in fact, collaborated recently with Mr. Allison and Medarex -- he and two colleagues published a pessimistic essay in the journal Nature Medicine in September. Its message seemed to reverberate through the halls of last month's conference, even in Dr. Rosenberg's absence. The three scientists cited their own research since 1995 on many experimental cancer vaccines in 440 patients, and reported an overall success rate of only 2.6 percent. In 35 other studies, involving 765 patients, only 29 people, or 3.8 percent, experienced at least a 50-percent reduction in the size of their tumors, the essay said. (Dr. Rosenberg qualified that assessment by noting that he had not looked at studies of blood cancers, like Dr. Levy's.)

"In light of these very large numbers of patients treated with vaccines and the exceedingly low objective response rates," Dr. Rosenberg and his colleagues wrote, "... a re-evaluation of future directions for cancer immunotherapy trials would be valuable."

He thinks a better strategy may make use of the immune system, but not by calling on it to mount its own defenses. Instead, he advocates removing immune cells from patients, making them reproduce in the lab, and then injecting them back into the patient. The effect is to increase the sensitivity of the immune system.

The process of identifying the cells and growing them is complicated and takes six to seven weeks at this point. He hopes that, as research progresses, the process will become easier and faster.

So far, the injected cells have been more successful than vaccines. In 2002 he published a paper reporting that tumors had shrunk in 6 of 13 patients with metastatic melanoma. He has a paper accepted for publication reporting a larger trial, with 35 patients, which also shows shrinking tumors in around half of the patients.

But scientists shouldn't turn their backs on vaccines just because Dr. Rosenberg's therapy, immune-cell transfer, has produced positive results, Dr. Odunsi told the conference attendees. "I think it's really premature to say that cancer vaccines have failed," said the Roswell Park researcher.

"That's not the message at all," Dr. Rosenberg responds in an interview. "The only message is that as of now, we haven't figured out how to make it work."

Both scientists emphasized the need to investigate the immune system further. Researchers are still discovering the cells and molecules that can activate the immune system or, conversely, put a brake on its defenses. And researchers still do not understand why some people's cancers disappear, and others' don't, when they receive vaccines or other therapies to harness the immune system's strength.

One day, researchers think, they will know how best to prompt the wrath of the immune system against tumors. The promise of immunotherapy is that once the immune system has eliminated intruders, it will stay ever watchful, maintaining its defenses against future cancerous assaults.

Using the Body's Resources to Attack Tumors

Scientists have tried several strategies to harness the immune system to fight cancer. Among them are:

  • Using tumor antigens. The surfaces of cancerous cells have protein fragments called antigens, which can differ from those on the surfaces of normal cells. A vaccine containing those tumor antigens could teach the immune system to recognize and destroy the tumor and leave healthy cells alone.
  • Devising personalized vaccines. One scientist is making vaccines by using so-called heat-shock proteins from patients' own tumors. The heat-shock proteins envelop tumor antigens and make the immune system more aware of them.
  • Lifting the immune system's brake. The immune system has its own brake, a molecule called CTLA-4. One scientist is working to disable the molecule, freeing the full power of the immune defense.
  • Using cell transfer. Perhaps the immune system just needs more warrior cells to defeat a tumor. Some researchers are removing immune cells from patients, growing them in the lab, and injecting them back into the patient.

SOURCE: Chronicle reporting

Section: Research & Publishing
Volume 51, Issue 12, Page A22