It seemed like such a sensible way to fight cancer: Enlist a patient's immune system to attack malignant tumors. But sensible doesn't necessarily mean easy -- and scientists' attempts to elicit such a tumor-fighting response have been fraught with disappointment for decades.
Today, however, as scientists gain a deeper understanding of how the human immune system works, a new generation of experimental cancer vaccines are showing promise as potentially safer and more effective treatments for many types of malignancies.
Researchers at major medical centers across the country -- including several institutions in Southern California -- are reporting encouraging results in human clinical studies of cancer vaccines. These vaccines currently are available only to patient volunteers in research studies, and scientists have more hurdles to overcome before such treatments become standard practice. If all goes well, however, the first of these vaccines could receive federal approval within the next few years.
Unlike the scattershot effect of chemotherapy or radiation, which kills both healthy and cancerous tissue with significant side effects for patients, these vaccines are designed to destroy only malignant cells. These therapies don't offer a cure for patients and they don't prevent disease, like conventional vaccines. But experts hope that eventually these therapeutics may be powerful enough to destroy tumors and prevent recurrences of the disease -- without the debilitating side effects of current treatments.
"This opens up a whole new front in the war on cancer," says Dr. Heinz-Josef Lenz, an oncologist at USC/Norris Comprehensive Cancer Center in Los Angeles.
Chuck Bittick, for one, believes that an experimental colon cancer vaccine will help him beat the odds. Last June, Bittick, 63, was diagnosed with advanced colon cancer that had spread to his stomach, a condition that typically is fatal within two years. After surgery failed to remove all his cancer, he felt standard therapy didn't offer him much hope. So the Yorba Linda man volunteered for a national clinical trial in which a cancer vaccine was used in combination with chemotherapy. (Federal rules require that patients participating in research studies receive proven treatments before they receive experimental therapies.)
For four months, Bittick traveled to USC/Norris for weekly chemotherapy treatments and vaccine injections every six weeks. Within 12 weeks of beginning therapy last September, his cancer disappeared. "I thought my life was going to be over in a couple of years," says Bittick. "Now I just want to get back to surfing and being normal."
Researchers can't say for sure whether the vaccine eradicated Bittick's tumor. USC's Lenz, a researcher in the trial, said it is "very rare" to see that degree of tumor shrinkage in such a short time with patients given chemotherapy alone. "We think the vaccine worked synergistically with the chemo," he says.
Scientists are testing these treatments on patients with advanced cancers who have exhausted conventional treatments. But they also are hopeful that these therapies someday may be used to treat cancer patients at an earlier stage, when their immune systems haven't been depleted by fighting off the tumors, or ravaged by toxic chemotherapies.
"The most benefit from these therapies will probably be after surgery, to prevent a relapse," says Dr. Johannes Vieweg, a urologist and immunologist at Duke University in Durham, N.C., who is testing a vaccine for prostate and kidney cancer.
Scientists long have been intrigued by the idea of rallying a patient's immune system in the battle against cancer because they knew the immune system often eliminated small tumors on its own. "We occasionally see spontaneous remissions, particularly in melanoma and kidney cancers," says Vieweg. "The body can cure itself."
A smarter immune system
The scientific challenge was to teach the immune system to attack cancer cells. Since cancerous cells arise from the same tissue as normal ones, these malignancies evade detection by the immune system, which fails to recognize that the malignant cells are dangerous. Tumors also outwit the immune system by partially camouflaging their abnormal surface proteins, which makes them virtually invisible.
Consequently, the immune system had to be trained to distinguish mutant cancer cells from normal cells, and thus be spurred into action. Previous cancer vaccines, in which patients were injected with their own tumor cells, didn't work because only a fraction of the cells injected were able to survive.
"A lot of what we were doing five years ago we can throw out the window and attribute to naivete," says Dr. John A. Glaspy, an oncologist at UCLA's Geffen School of Medicine who has tested a vaccine on women with advanced breast cancer. "The immune system is very complex, but we have much more insight now into how it works. I'm optimistic that this time, we'll get a hit."
One significant milestone, says Glaspy, was the discovery of how white blood cells called dendritic cells orchestrate the immune system's response to invaders. Dendritic cells hide in the bloodstream or other parts of the body, such as the skin, patrolling for suspicious pathogens.
Once a dendritic cell spots alien microbes, it engulfs them, chemically shredding them into fragments called antigens. The dendritic cells display these antigens on their surface to the T-cells, a principal type of white blood cell that helps protect the body from foreign agents, such as infections. Exposure to these antigens activates the T-cells, which go on a search-and-destroy mission to find cells in the body that carry that particular antigen. "No one understood before how T-cells are programmed to attack a particular invader," says Glaspy.
This knowledge has been used to devise promising vaccines to combat non-Hodgkin's lymphoma, melanoma, multiple myeloma and prostate, breast, ovarian and kidney cancer. Dendritic cells from a patient's immune system are primed in the laboratory with bits of their own tumors, which have a specific antigen that, like a fingerprint, is unique to each patient. Inoculating these patients with antigen-bearing dendritic cells helps their immune system identify cancer cells.
"Tumor cells all wear the same 'black hat' or antigen," says Dr. John P. Leonard, an oncologist at Cornell University's Weill Medical College in New York who is testing a vaccine for non-Hodgkin's lymphoma. "We're training the immune system to kill every cell it encounters that's wearing that black hat."
Vaccine easy to tolerate
Since the cells come from the patient's body, there is no risk the body will reject them and induce severe side effects. In fact, one benefit of these vaccines is that they're easily tolerated, unlike chemotherapy.
Patricia Melchiorre, one of 480 volunteers in a nationwide test of the lymphoma vaccine, says side effects from her treatment have been so mild that she hasn't missed a day of work as a teacher's assistant in Mount Laurel, N.J. Melchiorre was diagnosed in 2000 with advanced lymphoma. Chemotherapy left her nauseated, some of her hair fell out, and she was too exhausted after treatments to do anything for at least a day or two. The vaccine "is a vast improvement," says Melchiorre.
Early studies suggest these new vaccines work. Duke University researchers, for example, gave three doses of a dendritic cancer vaccine to 13 patients with advanced prostate cancer that had not responded to conventional treatment.
Blood tests in all of the men showed that the vaccine had successfully boosted the immune system, and six patients' tumors shrank. These scientists had similar success with metastatic kidney cancer patients.
"The tumors don't grow for extended periods," says Vieweg, which suggests a small but significant effect on tumor growth. To see any effect on people who are terminally ill, he says, is unusual.
Another vaccine approach, known as adoptive transfer, has been tested on 13 patients with metastatic melanoma, a deadly skin cancer that hadn't responded to standard treatment. A fragment of each patient's melanoma tumor was used to grow T-cells in the laboratory. Exposure to the tumor activated these immune cells so they would recognize and destroy the cancer cells when they were injected back into the patients.
In a study last year involving patients with very aggressive cancers, doctors found that the treatment shriveled the size of tumors by half in six patients, while four others had some cancer growths disappear. Of the 13 volunteers, all very seriously ill, 10 were alive six to 24 months after the first treatment. "We've gotten extraordinary results in patients with advanced tumors that had been resistant to other treatments," says Steven A. Rosenberg, chief of surgery at the National Cancer Institute in Bethesda, Md., and the lead investigator on this study.
Despite these successes, experts say more studies are needed with larger groups of patients to demonstrate effectiveness and evaluate side effects.
"We're still not ready for prime time, but we're light years ahead of where we were before," says Glaspy. "I'm convinced that someone will hit oil soon."
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How it works
Scientists are testing a new generation of cancer vaccines that use a person's dendritic cells, a type of white blood cell, to stimulate the body's immune system. Normally, the immune system has trouble recognizing tumors because cancer cells arise from the same tissues as normal cells. But these vaccines "train" the immune cells to distinguish malignant cells from normal ones, and to attack only the cancer cells.
1. Doctors extract a number of dendritic cells, which normally patrol for disease-producing agents.
2. Bits of the patient's tumors, containing antibody-producing antigens, are exposed in the laboratory to dendritic cells, which pick up the antigens.
3. The antigen-bearing dendritic cells are injected back into the patient. They then display the antigen to the killer T-cells, which become activated to hunt down cells in the body that carry that particular antigen.
4. Unlike chemotherapy or radiation, these vaccines do not destroy healthy
cells or have debilitating side effects.