Research seeks vaccine that would turn immune system into cellular assassin

March 2, 2005

For 12 years, Barbara Howell was cancer-free. Or so she thought.

Her very small tumor was diagnosed when she was only 36. "I had a mastectomy. The doctors told me all was well, to go ahead and live my life."

Graphic: Cancer protection

Which she did until 1998 when she ended up in the hospital with an invasion of cancer into her bones. "I had multiple fractures, although remarkably I wasn't in any pain. I had metal rods put in all my long bones. The doctors promised me a plate in my head and surgery in my spine and said I'd never walk again. They said I'd probably be dead in three months."

Howell, a financial manager in San Diego, beat the odds, eventually walking again. She now acts as a mentor to cancer patients, talking about survival. But she's learned a sobering lesson.

"It's recurrent," she says. "I don't care who you are, if you've had cancer, you're going to have it again."

It is the wily nature of cancer to escape treatment and fly under the radar screen of the body's healing responses. What's needed is a way to fire up the immune system to attack lingering cancer cells. What's needed is a vaccine.

More than 100 clinical trials of cancer vaccines are progressing across the country, spurred by new advances in vaccine delivery and better knowledge of the immune system. The hope is that one or more could prevent stories like Barbara Howell's.

"We can potentially convert a lethal disease into a chronic one," explains Dr. Albert Deisseroth, president of La Jolla's Sidney Kimmel Cancer Center and the principal investigator for a vaccine for breast and prostate cancer that will begin clinical trials in December.

"We may not be able to get rid of all the cancer cells. But if you're 60 years old and get cancer and you take a vaccine and get rid of the aggressive cells, then the others can sit there for 15 years and not do anything. And who cares?"

It's intolerable

The sole cancer vaccine approved by the Food and Drug Administration targets the hepatitis B virus, associated with liver cancer. Another vaccine made by Merck for cervical cancer – most of which is caused by human papillomavirus – has entered large-scale human trials with tens of thousands of women worldwide. These fall into the category of preventive vaccines; they work by stimulating the creation of antibodies that recognize and attack viruses.

Vaccination – widely considered the most important medical advance in the history of medicine – dates back to Edward Jenner, who in 1798 determined that inoculation with cowpox, which is benign in humans, creates an immunity to the potentially fatal smallpox virus.

Most cancer vaccines will depart from this approach. At least in the beginning, they won't prevent cancer. They will treat it.

"These vaccines are meant to stop tumors from growing once they have formed," explains Jeffrey Schlom, chief of the Laboratory of Tumor Immunology and Biology at the National Cancer Institute.

So-called therapeutic vaccines will be used in patients with recurrent cancer to stimulate the immune system not against an infection, but against regrouping cancer cells.

Researchers used to think that a faulty immune system was responsible for some cancers: If all was functioning properly, the immune system would target and kill malignant cells. Now it's clear that thinking is only partially true.

In fact, the immune system has a hard time distinguishing cancer cells. On their surfaces, cancer cells and normal cells resemble one another. To function properly, the immune system must not only attack foreign invaders, but preserve normal cells – a process known as tolerance. Even healthy immune systems often tolerate cancer cells.

The idea behind cancer vaccines is to make the immune system intolerant to cancer, to mobilize it to attack tumor cells the way it would avenge a cold virus or a sinus infection. Therapeutic vaccines would not only elicit an antibody response, but marshal an army of killer T-cells to attack tumor cells. It would be global warfare, all forces mobilized.

"The immune system is designed to dramatically and quickly respond to a viral infection," Deisseroth explains. His vaccine, which will be tested in 48 prostate and breast cancer patients in San Diego, "is a way to trick the immune system into believing a viral infection is under way, so the whole immune system gets mobilized against tumor cells."

Compared with chemotherapy and radiation, vaccines are easy to administer and nontoxic. Dr. Charles Butts, an oncologist at Cross Cancer Institute in Edmonton, Canada, has gotten promising results from a prostate cancer vaccine. "It's simple to deliver," he says. "An injection under the skin on a weekly or every-six-week basis."

Explains Schlom, "This is a very different paradigm. Unlike toxic drugs, which either kill or don't kill tumors, the activation of the immune system is a dynamic process."

When the immune system has learned to recognize tumor cells as foreign, it will achieve stasis with cancer, researchers believe. "There's a high probability that everyone is living with the herpes virus that causes cold sores," Schlom says. "Every once in a while it will flare up, but the immune system keeps it in check. That's what vaccines promise."

Early studies

It's been working in mice. Deisseroth and others have been able to create cancer immunity in mice for over a year with virtually no side effects.

In humans, most trials are in the early stages, testing safety and dosage levels in small numbers of patients. An exception is Canvaxin, a vaccine that has extended survival in melanoma patients. Carlsbad-based CancerVax Corp. has just enrolled over 1,000 patients in a phase 3 trial, the last step before being able to apply for FDA approval.

Last month, researchers at UC San Francisco announced that a vaccine called Provenge, developed by Seattle's Dendreon Corp., extended survival in 82 men with advanced prostate cancer. A Canadian vaccine, BLP25, tested by Butts, extended survival by four months in 170 patients with advanced lung cancer."In my mind, it's one of the most promising results," Butts says.

At the NCI, a vaccine developed by Schlom is in phase 3 trials, which should finish in a year with several hundred patients with pancreatic cancer. The vaccine, called PANVAC, was developed with Therion Biologics of Cambridge, Mass.

"We're seeing two things," he explains. "One is that the vaccines have minimal toxicity and the other is that patients seem to be living longer with their tumors. We can't prove it yet, but we can be cautiously optimistic."

Developing targets

Cancer vaccines capitalize on the fact that certain molecules on the surface of cancer cells are different or more abundant than those on normal cells. These are known as antigens. Weak antigens don't provoke the immune system; strong ones do. The challenge is to change cancer antigens from weak to strong.

The earliest vaccines, including CancerVax's Canvaxin, use an approach called whole-cell, in which tumor cells from one or more patients are altered in the lab and re-injected in patients to stimulate an immune response. These might go to work on dozens of antigens at the same time, a sort of scattershot approach.

Schlom terms some of these "your father's vaccines. They have been around for a long time and many have not worked. But some of the newer modified ones may work."

Newer strategies are homing in on specific antigen targets. Among the most promising is the molecule MUC-1, which was discovered in human breast milk in 1982.

Rod-shaped MUC-1 is found in normal cells that line organs that have airways, tracts or ducts. The lining of these organs are coated with mucus, a thick, syrupy substance that protects against infection and damage, say from rough food passing through the stomach. MUC-1's job is to stabilize the mucus.

When cancer is present, MUC-1 molecules increase and change, for reasons not completely understood. The rods change location, and sometimes parts of them go missing. This occurs in all so-called epithelial cancers – prostate, colon, breast, lung, pancreas, stomach, ovary, esophagus, endometrial and rectal, which together account for about half of all new cancer cases and deaths.

Cancer patients with high levels of MUC-1 have poorer survival, increased metastases and greater resistance to chemotherapy and radiation.

"We've chosen MUC-1 because it's a marker for the bad guys," explains Deisseroth. "And it's a marker for cancers that are the biggest killers in the United States."

Delivering the goods

MUC-1 gives researchers a target; the challenge is how to get the immune system to recognize and respond to it. One way is to use a virus or a vaccine as a way to deliver MUC-1 to the immune system.

Schlom's vaccines for pancreatic and prostate cancer combine the smallpox vaccine, used to prevent smallpox, with genes that express MUC-1 and another antigen, CEA.

Deisseroth's vaccine is a combination of a piece of MUC-1 molecule and a cold virus.

The vaccine and the virus work in the same way – they trick the immune system into believing an infection is beginning. To the immune system, the infection "looks" like MUC-1.

"We're imprinting on the immune system the tumor marker, so the whole immune system gets mobilized against the tumor cells," says Deisseroth.

Once vaccinated, the body will hopefully trigger its well-oiled immune response. Dendritic cells – the early warning system – will travel to the lymph nodes, which will respond by arousing T-cells, which will spill out into the bloodstream to hunt down and kill cancer cells with MUC–1.

The body will now recognizes MUC-1 as an invader, and will mount continual attacks against it. Based on his mouse studies, Deisseroth believes that after three vaccinations, immunity will last a year.

Deisseroth has designed his study for patients in the beginning stage of relapse, which in prostate and breast cancer can be measured with blood tests. The rationale is that the fewer cancer cells, the better the immune system's chances of winning.

"It's a race between how fast the T-cells can expand – how many soldiers you can put out onto the battlefield and how fast the tumor is growing," he explains.

Butts' study showed that lung cancer patients with less severe disease survived longer after vaccination.

"I liken it to hand-to-hand combat," says Schlom. "If you have a 1,000 T-cells and 1,000 tumor cells, then you've got a good chance – in contrast to having, say, 1,000 T-cells and a billion tumor cells."

As promising as it seems, early success in clinical trials may not be borne out in subsequent, larger studies. MUC-1 may not even turn out to be the optimal target. At Memorial Sloan Kettering Cancer Center in New York, Govind Ragupathi is developing a vaccine directed at eight antigens.

"Is there one antigen that's right?" he asks. "The answer is we don't know yet. If you take a cancer cell, it is not expressing one antigen, it's expressing many. My belief is that targeting one antigen is not a good idea."

As cancer is not one disease, but many, treatment vaccines will no doubt number more than one. "There is really no competition between vaccine A and vaccine B," explains Schlom. "What we've learned about chemotherapy is that a combination of drugs works better than a single drug. The same will be true of vaccines."

In contrast with drugs that either work or don't, vaccines offer the infinite possibility of refinement, he says. Data from clinical trials will allow researchers to tweak the brew: add or substract antigens or genes; alter delivery systems; add substances to further stimulate immune response.

None of this will happen quickly. In five years, Schlom predicts maybe four vaccines will be on the market. Deisseroth will need at least that long to finish phase 3 trials of his vaccine for breast and prostate cancer.

Now he's anxious to get started. "I'm the kind of person who tries to create the biggest value for the most people. I feel I have a moral obligation to get this into the clinic as fast as we can because I think it's going to work."