Vaccinating Against Cancer

For more than a century researchers have hoped to enlist the body's immune system in the fight against cancer, but the markers that identify a tumor as alien long eluded them. Now, by a combination of accident and relentless logic, several researchers are closing in on ways to force tumors to show their true colors to the body's immune system.

IN December of 1982 a young German physician named Alexander Knuth climbed into his car and set off on the three-and-a-half-hour drive from Frankfurt to Brussels. Carefully tucked into his shirt pocket, so that his body heat would keep it warm, was a flat plastic flask known as a cell-culture bottle. The flask contained cancer cells isolated from one of Knuth's patients, a German postal worker we will call Frau H., who at the time was losing ground to a rapidly advancing form of skin cancer and was not expected to live much longer.

Several months later Knuth sent to Brussels, in a container packed in dry ice, a small quantity of Frau H.'s white blood cells -- the portion of blood that includes the most potent cells and molecules of the immune system. In those two consignments were the cellular protagonists in one of the deepest, most complex, and often most heartrending dramas in human biology -- the battle between the immune system and cancer. Those particular cells would figure in a marvelous scientific saga that more than a decade later has given a new twist to a very old form of medicine: vaccination against a disease after it has been diagnosed in the patient.

Working in a two-person laboratory at the University of Mainz, Knuth had noticed that Frau H.'s white blood cells, and by implication her immune system, seemed to recognize her cancer cells with exquisite specificity. No tools existed at the time, however, to record the full richness of the relationship between white blood cells and cancer cells -- a relationship typified by behaviors we usually ascribe to psychology: recognition, evasion, tolerance, even mortal violence. Knuth didn't know exactly what those immune cells recognized. He did, however, know of a researcher who had painstakingly been developing the technology to help him figure it out.

For more than a century doctors have nourished the hope of enlisting the immune system in the battle against cancer -- specifically, of manipulating the immune system so that it will track down and eliminate tumors and the spreading seeds of malignancy, known as metastases, in much the way it tracks down and eliminates viruses and other pathogens. Crucial to this effort has been the belief that tumors display antigens -- distinct molecular landmarks on their cell surfaces -- that betray the malignant nature of the cell within and might therefore incite an immune response. For many years researchers have presumed that tumor antigens useful for a vaccine strategy exist, but these have stubbornly eluded scientific capture. Although a long history of anecdotal evidence has suggested that the immune system has in some rare instances caused certain cancers to disappear on their own (melanoma and kidney cancer among them), attempts to translate that evidence into useful therapies have produced chiefly disappointment.

Cancer remains little affected by immunological approaches -- indeed, by most of the current kinds of treatment, with the possible exception of surgery. About 1.4 million Americans are found to have cancer each year, and nearly half these cases prove to be incurable, usually because the disease has spread too far by the time of diagnosis. According to George Canellos, a professor of medicine at Harvard Medical School, about 50 percent of people with cancer survive for five years after diagnosis and are considered cured, but the vast majority of those cures are achieved with surgery. Only about 10 percent of patients are cured by radiation alone, and only five percent by the combination of radiation and chemotherapy. Except in childhood cancers and a few adult malignancies, chemotherapy alone rarely produces a five-year remission.

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These sobering statistics fall within the shadow of a larger, and unfortunate, public perception that was shaped in part by Richard Nixon's declaration of war on cancer in 1971. The inevitable implication of Nixon's declaration was that cancer, presented for the sake of political convenience as a single enemy, might finally be conquered by a single cure. If any lesson has become clear in the past twenty-six years, it is that cancers arise from a multitude of circumstances, in many kinds of cells, by way of a large number of molecular pathways, and that they respond to many different treatments. Another powerful message is that once a cancer spreads, neither surgery nor radiation, and only occasionally chemotherapy, can turn the tide -- which is why enlisting the help of the immune system remains such an attractive alternative. "I think it's the only chance we really have to control systemic disease," says Ronald Levy, an oncologist and cancer researcher at Stanford University. "Because the real problem in cancer is metastatic disease, micrometastatic disease. It's the reason we don't cure people now."

Alexander Knuth's initial journey to Brussels might have been viewed -- indeed, was viewed by some of his German colleagues -- as the latest in a long succession of fool's errands in the field of tumor immunology. Once in Brussels, Knuth passed on Frau H.'s cancer cells to Thierry Boon, a Flemish-born, French-speaking, American-trained medical-school dropout who headed a large laboratory at the Catholic University of Louvain, funded by the Ludwig Institute for Cancer Research. Boon had become fascinated -- almost against his will, to hear him tell it -- with the immunology of cancer, which, after decades of search for those elusive antigens, was in considerable disrepute around the time his interest was piqued. Boon, Knuth, and their colleagues in Brussels and Frankfurt set out to understand the relationship at the molecular level between the immune system and cancer cells -- what the immune system perceives and in what context, how it is able to distinguish a cancer cell from a healthy cell, and how the tumor responds to intense and potentially lethal scrutiny.

Frau H.

THE was a dark-haired, somewhat plump woman, thirty-seven years old and the mother of two teenagers, who intensely disliked her job sorting mail during the early-morning shift at the local post office in a small town just southwest of Frankfurt. The tragedy that ultimately led to Frau H.'s exalted status in the world of tumor immunology announced itself in a whisper of minor symptoms: fatigue, vague abdominal distress, cramps, pallor. As her health declined, she spent entire days lying in bed. Finally, after Frau H. consulted her regular physician in March of 1982, doctors at her community hospital suspected she had developed several large cysts, probably cancerous in origin, and sent her to the Department of Gynecology at the nearby University of Mainz for surgery. The "cysts" turned out to be three tumors, one in her ovary and two in her adrenals; the latter two were later estimated by her doctors to be about the size of grapefruits.

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