Cancer vaccines showing promise

Treatment aimed at current patients

3/13/2003

oston doctors are preparing to test a promising experimental lung cancer vaccine on dozens of patients at local hospitals, part of a booming research effort that seeks to kill cancers through simple pinpricks.

More than 80 cancer vaccine trials are unfolding around the country, according to federal health data, including 12 underway in Boston hospitals, offering potential treatments for ovarian, skin, blood, colon, cervical, and lung cancer.

Unlike conventional vaccines that prevent disease from striking in the first place, cancer vaccines are aimed at people who have already been treated for cancer with hopes of avoiding the tumor's return. Researchers use various methods to alert the body's immune system to the presence of cancerous tumors, which normally grow undetected by the body's natural defenses.

In one of the more striking results to date, two lung cancer patients at Dana-Farber Cancer Institute who had been expected to live less than a year were still tumor-free after more than three years. Researchers found that patients in the vaccine test developed powerful immune reactions against their tumors, though most of the patients subsequently died. A larger second phase of the trial is expected to start this fall.

The notion that vaccines, so successful against simple viruses, could fight complex cancers was ridiculed when first proposed a century ago, and the field was considered a backwater even a decade back. But vaccine research, building on early successes in preventing the return of a deadly form of skin cancer, is now a vital component of cancer research around the world, said specialists.

''It's quite possible that people could live with their tumors in quite a healthy state with a vaccine,'' said Dr. Jeffrey Schlom, who monitors research nationwide as chief of tumor immunology for the National Cancer Institute, adding that ''the field is still very young.''

Most researchers are thrilled by recent breakthroughs, but acutely aware that many of the trials are in the earliest stages of human testing. ''You don't want to raise hopes too much on treatments that may not turn out to work,'' said Dr. Alan Houghton, the immunology chairman at Memorial Sloan-Kettering Cancer Center in New York, where much of the pioneering research unfolded. ''But my feeling is that at some point, it may be years, it may be decades, but at some point, these vaccines will play an important role in cancer therapy.''

Dr. Glenn Dranoff, architect of the Dana-Farber lung cancer vaccine test, shies away from publicity about his work. When word gets out, he knows the calls will come from desperate patients convinced that simple injections might save their lives.

Dranoff's work exemplifies the recent leaps made in cancer vaccine research. In the 1990s, he designed a vaccine for the most dangerous type of skin cancer, melanoma, helping the body's immune system recognize cancerous cells.

Cancer cells are much harder for the immune system to detect than viruses that are typically the target of vaccines. Cancer cells are normal body cells with a few defects that make them multiply uncontrollably into dangerous tumors. But the defects are too subtle to be detected by the immune system. So Dranoff decided to paint a genetic bull's-eye on them. First he removed melanoma tumors from patients. Then, in a lab dish, he infected them with a harmless virus that he engineered to carry a gene called GM-CSF. This gene alerts the immune system to intruders. The infected tumor cells - after being treated with radiation that prevents them from becoming cancerous again - were injected into patients' arms and legs.

Dranoff's theory: The GM-CSF gene would attract an immune attack and, in the process, the immune system would learn to recognize the tumor cells wherever they might be in the body. Unlike traditional cancer treatments, such as radiation and chemotherapy, the immune cells could attack cancers at the earliest stages of growth - before they can even be detected. The technique at work, known as gene therapy, is a controversial but promising approach that harnesses recent discoveries about human genetics.

When the first test of the vaccine ended in 1998, Dranoff's team examined their patients and found the melanoma tumors in most had been vigorously attacked by the immune system. It was not 100 percent effective, but it was proof positive the method worked. Further melanoma tests were launched. Some of Dranoff's colleagues thought his team should turn its attention to more widespread and deadly cancers.

Lung cancer, said Dranoff, seemed an ideal target. ''Lung cancer in our country is the major cause of cancer death,'' said the soft-spoken Dranoff recently. ''But it has hardly been studied by vaccine researchers.''

He used the same gene therapy technique on 25 patients suffering from non-small-cell lung cancer, injecting each weekly with his lung cancer vaccine. This cancer type accounts for 80 percent of all lung cancers. Each patient had already failed several other standard therapies and had less than a year to live.

In 18 patients, the vaccine produced significant immune system responses against the tumors. Six patients had their tumors surgically examined; in three of those cases, immune system cells had invaded the tumors, killing thousands of cancer cells.

Two patients had no tumors left to be tested, and were cancer-free even three years after the injections.

Cancer in five of the 18 patients stabilized for up to 33 months.

But there was also ample evidence of lung cancer's deadliness: rapidly spreading cancer forced nine initial test patients to withdraw from the trial, and today, six years after the trial began, only three of the original 18 patients remain alive. ''It is important to be very conservative in reporting the results of the trial,'' said Dranoff, with typical caution. ''It is encouraging that the vaccination approach proved feasible, safe, and capable of enhancing the immune response to lung cancer cells.''

His team is preparing a trial on a larger scale, to begin this fall, to further test the vaccine's efficacy when combined with other cancer drugs. An even larger version of the trial, with hundreds of patients, will be run by the California-based biotechnology firm Cell Genesys Inc., which works closely with Dranoff.

Though much of the most promising work remains in melanoma treatment, that is changing. ''Recently more and more work is being done on a large population of tumors: breast, lung, colon, and prostate,'' said Schlom.

Schlom said the vaccines are likely to prove most effective in the early stages of cancer, when the immune system is still robust. However, because of ethical rules, only the sickest patients currently can be tested with the vaccines. Therefore vaccines' effectiveness in early-stage patients, when they are likely most potent, remains untested. ''It's a very, very slow process,'' said Schlom.

However, within two years, federal regulators predicted numerous Phase III vaccine studies, the final step before government approval, will be underway.

But there have been setbacks. Cancer cells are extremely elusive targets, constantly changing their genetic makeup.

Houghton recently finished a Phase III skin cancer vaccine trial, using a differnt approach from Dranoff, that found conventional treatment worked better.

''I really don't know which vaccines will work,'' he said.

Still, the field has been significantly advanced in the last five years. In the early 1990s, skin cancer vaccine research made up more than 90 percent of the field, said specialists, simply because melanoma tumors, which appear on the skin, were easier to study. But researchers, capitalizing on recent advances in genomic science, began identifying genetic targets on other cancers that vaccines could take aim at, jump-starting the field. ''Ten years ago, people had real doubts,'' said Dranoff. ''But once you have targets, you can use the same techniques used to fight other infections.''