Where radiation and chemotherapy fail...

Where radiation and chemotherapy fail, this new treatment is helping people beat back lethal cancer.

The banker, the jockey, the college president, the social worker . . .

Young and old, male and female, from Sun Belt and Wheat Belt, they were all diagnosed, some years ago, with an advanced form of the aggressive skin cancer known as malignant melanoma. Indeed, they were all made to understand that their remaining days would probably be measured in months, not years; that their affairs should be tidied up, their final goodbyes composed in that benumbed, disbelieving solitude of the terminally ill. More than politics, even, disease makes strange bedfellows, and what these four people had in common was the random and seemingly hopeless fellowship of imminent death.

"Doctors told me I might as well enjoy myself--I probably had six months to a year," says Laura Abrams, who manages assets in the San Diego office of a major bank. If there is a tincture of triumph in Abrams's voice, it is because she recently celebrated the eighth anniversary of getting that bad news. Now her battle is not so much with cancer as with the psychological side effects of surviving cancer for so long: worrying about getting old and feeling guilty about it, fretting over her wrinkles, burying deeper in her psyche the persistent fear that the disease could recur at any time. Abrams is among a handful of patients--more than a thousand since 1985 or so-who have received one of several experimental cancer vaccines that are under development. More to the point, she is among a minority of vaccine recipients who appear to have responded spectacularly to the treatment.

These experimental vaccines are but one small piece of a broad and encouraging new approach to disease that falls under the umbrella term of immunotherapy. This deliberate manipulation of the immune system utilizes its special abilities--its exquisite sonar for things foreign and threatening--to identify and eliminate disease. Part of the growing interest in these so-called biologic approaches is by default: Conventional cancer treatments like radiation and chemotherapy cure relatively few people, at great cost to many in.terms of toxic side effects. And part of the interest is almost philosophical: There has always been an appeal in "natural" agents, even though the use of such immune-based molecules as interferon and interleukin-2 has produced as much frustration as promise. What tantalizes and teases researchers, doctors, and patients alike is the kind of medical epiphany experienced by Laura Abrams and her physician back in the summer of 1986 in a small hospital examination room in East Los Angeles.

Abrams had discovered a bleeding mole on her right leg in February of 1985. In less than a year, telltale, raisin-sized lumps had cropped up just beneath the skin of her leg, indicating that the melanoma had spread. By the following spring, hundreds of small tumors began to appear. Her doctors were even more chagrined to discover--in the ominous patois of oncology-a "lung met." The melanoma had spread, or metastasized, to the lung, forming a hive of a billion or so cancer cells, which cast a grape-sized shadow on her chest X ray and a much larger one on her life expectancy.

It was then that Abrams learned of an experimental melanoma vaccine developed by Malcolm S. Mitchell, a researcher at the University of Southern California/Norris Cancer Center and its former chief of medical oncology. In June of 1986, Abrams drove up from San Diego and received her first shot of Mitchell's vaccine. To hear her tell it, the worst side effect of the treatment was dealing with freeway traffic.

Abrams came in for a follow-up visit seven weeks after starting the vaccine. "I remember standing in the dressing room with my X rays, undressed, looking at them," she says. "And there was nothing on them." Abrams, now 42 years old, describes this moment while sitting in her office, 18 floors above downtown San Diego, and her voice suddenly becomes hushed, her eyes a wet reflection of the downpour outside.

"I went out," she continues in a whisper, "and I said, 'Are these mine? You're sure you're not mistaken?'"

Mitchell, whose clock runs about half an hour later than the ones on the wall, hadn't yet arrived that morning, but another doctor assured Abrams that those were indeed her X rays. The lung spot was definitely gone. "I couldn't believe it," Abrams says now. "I still get teary-eyed when I think about it. I mean, they were all gone!"

Mitchell remembers the moment, too. Tumors that go away-and stay away--are as rare as religious miracles, and about as credible in medical circles. As he inspected the films, he strained to see some residue of the tumor. "I had seen shrinkage in one or two patients before her," he says now. "But never to this degree. Never that dramatic." True, the largest lumps on Abrams's leg required surgical removal, but even that brought encouraging news when lab tests revealed they had been infiltrated by tumor-killing cells of the immune system.

"When I saw that it was such a dramatic response, that hundreds of lesions had gone away, then I started to get very optimistic," Mitchell says. "From the scientific point of view, I knew that the vaccine was really worth something."

From the nonscientific point of view, it meant something immeasurably more important to Abrams: her future. As she puts it, "I started to think of life again."

There have been enough such moments--shrink-ages, disappearances, tumors stabilized, futures re-possessed--that in 1990, Mitchell began to invite many of his long-term patients, and a few newer ones, to an annual party at the cancer center. Laura Abrams calls it the Melanoma Club. There is food and drink, there's gossip about the nursing staff, and there is Mal Mitchell, in a photograph from the 1991 gathering, cutting the cake with all the gusto of a bridegroom, surrounded by half a dozen patients. What links them now is survival, of the sort that suggests that someday down the road, with more precise science and experience, currently lethal cancers like melanoma could be treated as manageable, chronic diseases, and possibly even prevented.

There were other pictures taken at that particular party-of the social worker, the banker, and the university president (the jockey couldn't make it; he was busy winning the sixth race at Santa Anita that day). But there is a problem with the photographs, and by extension with the vaccine; in fact, Laura Abrams can't bear to look at the photos anymore. The reason is that the vaccine seems to work in only one out of five patients, and nothing makes its limitations more obvious and more painful than a photo that shows a member of the club for whom it didn't quite work well enough.

On a typical morning, the 56-year-old Mitchell, having just arrived at work, will be fidgeting by the nurses' station. It seems that some of his patients, aware of his habitual tardiness, have decided to come in a little late themselves. "I feel like the third barber from the door, waiting for someone to come in," he announces. The nurses appear cheerfully unsympathetic.

As waiting rooms go, the one at Norris is said to be more comforting than most, but not everyone sitting there seems consolable. There is a woman in a blue housecoat, hands crossed, lips tight as a vise, staring out into the distance. There is a 68-year-old man still walleyed with disbelief that, after a lifetime as a self-described beach bum, a tan no longer signals vigor and health, but ominous and irreversible damage to the skin; his melanoma is far advanced, making him ineligible for a study currently under way. He is scheduled to receive another new biologic agent, interleukin-2.

All around them is that maddening hospital hubbub of orderlies bursting out one door, nurses disappearing swiftly through another, bits of gab and laughter trailing behind them, quick whiffs of normality whistling around this thick air of mortal introspection. Malignant melanoma has been increasing faster than any other cancer in the world. If the thinning ozone layer is contributing to the rise, as is feared, the future may see many more rooms like this, crowded with erstwhile sun worshippers alone with their well-bronzed disbelief.

One of the people in the room is a sandy-haired, fair-skinned 59-year-old man named Ronald Burman, who sits holding a large envelope of X rays. In February of 1989, doctors identified a deep melanoma tumor in Burman's right shoulder, with spreading tumors identified in his lymph nodes and lung-not good signs at all. In November of that year, after surgery, he began to receive the vaccine once a month. "Nothing dramatic happened to me," the phlegmatic Burman says now, as if the complete disappearance of an acorn-sized metastatic tumor in his lung were the norm.

Like most patients, Burman does not understand the world of modern immunology, with its language of T cells and tumor antigens. Asked to account for his continuing good health, Burman replies, "I guess it's the educated blood. The immune system, I guess, has been trained to find the melanoma." Although that's not a very revealing explanation, scientists can't do much better. No one has a thorough grasp of why these vaccines might be working.

The theory underlying a cancer vaccine seems at first contradictory. Most vaccines are commonly used to prevent diseases, not treat them. It was long believed that well-known vaccines against diseases like smallpox or polio achieved this preventive effect largely by stimulating antibodies, the immune system proteins that seize and then destroy foreign microbes. But in the last two decades, immunologists have begun to understand the equally important role of a second, cellular arm of the immune response: white blood cells, primarily T cells and natural killer cells. T cells, so named because they receive their education in the thymus, seem particularly adept at spotting unique molecular landmarks known as antigens on the surface of cells and then rallying the immune system bodywide to identify and destroy cells with the same telltale markings wherever they appear. Cancer vaccines seem to stimulate T cells to attack cancer cells, which recent research indicates have surface markings that differ ever so slightly from those of normal cells.

"People die because their cancer keeps spreading and goes to vital organs and kills them," says Mitchell. "Which surgery can't counter. Which radiation therapy cannot. But which immunotherapy, at least in theory, should do best of all because it uses immune cells that are designed for surveillance of the entire body."

The notion that the body could be tweaked into ridding itself of cancer dates back at least to the 19th century, before even the rudimentary components of the immune system were understood. In a horrific chapter in human experimentation, a few doctors in Europe deliberately infected cancer patients with the microbe that causes syphilis, for example, because tumors had occasionally been seen to shrink and disappear in syphilitic patients. In an age before antibiotics, the treatment was sometimes worse-or at least quicker--than cancer, and aroused considerable controversy.

And yet, on that invisible battlefield where immune cells encounter tumor cells, profound changes were known to occur. From 1893 to the mid-1930s, William B. Coley, a surgeon at New York's Memorial Hospital, treated hundreds of cancer patients with a vaccine-like preparation of killed bacteria known as Coley's toxins. A recent analysis that appeared in the British journal Nature suggested that Coley may have cured substantial numbers of cases of the cancer known as sarcoma. Five years after receiving Coley's vaccine and no other treatment, roughly half of 157 sarcoma and lymphoma patients available to follow up were found in this review to be free of disease. Cures lasting 20 years were achieved in approximately 30 of these "inoperable" patients.

Coley's toxins never received a proper clinical trial--that is, a rigorous scientific test in which patients are randomly assigned to receive one treatment or another to establish the effectiveness of a new therapy. His approach was eventually overtaken by expectations for chemotherapy and radiation, which were just coming into general use.

But it has now become apparent to many clinicians that, except for a few exceedingly rare cancers (most notably childhood leukemias and testicular cancer), chemotherapy often does little more than briefly extend survival. Meanwhile, experiments have shown that Coley's toxins stimulated dramatic changes in the immune system, including an increase in something called tumor necrosis factor (TNF), which can cause tumors to hemorrhage and liquefy.

Over the past four decades, biologists have isolated numerous potent molecules from the immune system--TNF, several interferons, more than a dozen interleukins. Each has been held to be more promising against cancer than the last; each by itself has eventually proved to be either too toxic or ineffective. But as if assembling single instruments piece by piece into a musical ensemble, researchers like Mitchell are tinkering with combinations of biologic agents, adjusting their sequence and dosages, and making slow but steady progress toward emulating the symphonic biology of the immune response.

For an apostle of immunotherapy, Mitchell traveled a very traditional route. He began his medical training at a time when radiation and chemotherapy were emerging as dominant cancer therapies. Later, as a member of the medical school faculty at Yale, he frequently resorted to chemotherapy in his practice. But with increasing reluctance. He published a series of papers in the 1960s and 1970s showing that chemotherapeutic agents can suppress the immune system. And although he continued to administer the drugs himself, he became disenchanted with them.

Chemo might cause tumors to shrink long enough to claim "responses" when it came to publishing studies, he found, but often the disease came roaring back a short time later. "You can see tumor shrinkage for two weeks with chemotherapy," he says, "but so what? If the cancer goes back to what it was before, then you've gained nothing."

Since late 1985, Mitchell and his colleagues have treated nearly 250 patients with the melanoma vaccine. Only about 60 percent of his patients become immunized--that is, they show detectable increases in killer T cells in response to the melanoma antigens in the vaccine. Only about a third of these patients--which is to say about 20 percent overall--have seen their disease respond. But among those who have, the median survival is better than two and a half years, compared to an expected survival of 12 months or less.

Other workers tilling the same ground have reported similar success rates. Oncologist Donald Morton, of the John Wayne Cancer Institute in Santa Monica, California, claims that 26 percent of his patients with metastatic melanoma survive five years on his vaccine, compared to an expected survival rate of 6 percent. At New York University, Jean-Claude Bystryn has reported extended survival of patients who respond to his melanoma vaccine. Vaccines are also being tested against colon, breast, and ovarian cancers, and a second generation of more sophisticated vaccines is just entering the clinic.

Nearly as remarkable, Mitchell's results have been achieved with minimal side effects, limited primarily to short-lived fatigue, temporary soreness at the injection site, and occasional cases of vitiligo, a condition in which the skin develops white spots apparently because immune cells attack pigment cells.

The benign nature of the treatment has allowed patients like Sandy Hawley to resume challenging, even harrowing, occupations. For his entire professional life, the name of the game for Hawley was to get to the finish line first, and for many years he has been without peer. In 1973, he became the first North American jockey to record more than 500 wins in one racing season. Then, in 1986, he was diagnosed with metastatic melanoma, and suddenly the name of the game became exactly the opposite: He desperately wanted this finish line to keep receding before his eyes.

In a medical sense, it has. When Hawley began taking the melanoma vaccine in 1987, his expected survival was six to 12 months, and although he still walks around with a pea-sized tumor in his lung, it has simply stopped growing. Sandy Hawley, meanwhile, has kept on riding and winning.

Since 1987, when he first began receiving the vaccine, Hawley has married and had a child. In 1992, he was inducted into the racing hall of fame. It is not possible to say categorically that he wouldn't be alive today without the vaccine, but it is certainly hard to imagine him, laid low by chemotherapy-induced anemia and diarrhea, clutching to a thundering thoroughbred on his way, yet again, to the winner's circle.

"Even though I am a card-carrying chemotherapist, it's just hard for me to recommend chemotherapy now," Mitchell says. "I still have to use it for some people, but it has become difficult to expose patients to the same range of side effects that I have gotten unused to-hair loss, bone marrow depression, loss of appetite, diarrhea, infections, things like that. You don't see that with immunotherapy."

The reaction of patients has been dutifully grateful, of course. Prolonged survival has restored control to patients whose medical situation seemed irretrievably out of control, Mitchell says, and many assert that regained power by, among other things, coming in for booster shots at their convenience rather than according to schedule. This includes an 85-year-old man who has been especially recalcitrant about appearing for his shots, although Mitchell believes the vaccine contributed to the disappearance of an extremely lethal form of melanoma that first appeared in his eye.

"This is the only case in the world, at least that I know of, of a tumor like this treated with immunotherapy," Mitchell says. "And it worked! It's been working for four years. And he doesn't understand. I told him, 'You know, you're unique in the universe.' And he said, 'Well, it's so hard to drive in from Pomona with the traffic. . . . '"

Larry Selland, who was named Idaho's Citizen of the Year in 1992, would in all likelihood have had much difficulty accepting the honor if the medical prognosis he received seven years ago had turned out to be true. In June of 1986, Selland, an administrator at Boise State University, discovered a lump in his groin that proved to be cancerous. Tests showed that it was metastatic melanoma. "I asked one doctor what I was up against," Selland recalls, "and he said I might survive six months." He began treatment with Mitchell's vaccine in March of 1987.

Perhaps the most remarkable thing about Selland's case is that, according to the criteria by which new cancer treatments are assessed, he was a failure--his melanoma did not disappear or shrink. In fact, it spread. By 1990, two nodules had appeared in his lungs. And yet he is alive and well and winning citizenship awards. When Boise State was plunged into chaos by the sudden dismissal of its president in the fall of 1991, Selland, still carrying those lung nodules wherever he went, stepped in to serve as interim president for 18 months and didn't miss a day of work. Now 57, he is a clinical failure who has survived seven years beyond the shadowy pall of statistics. Mitchell prefers to view Selland's experience not as a failure but as an example of the ways in which immunotherapy may operate differently-and therefore must be assessed differently-from traditional approaches to cancer treatment.

Many basic researchers believe too little is known about the way biologic therapies operate to claim with any degree of certainty that they work. According to these critics, some of the "responses" Mitchell has seen may merely reflect the natural course of the disease in a few lucky people. The criticism underscores the field's paucity of randomized trials, which typically require large numbers of patients, last a number of years, and can cost more than a million dollars. Only recently have drug companies been willing to foot the bill for such studies--a turnaround that reflects the increasing credibility of cancer vaccines.

Then there is the crudeness of his preparations; one well-respected immunologist privately refers to them as voodoo vaccines. To the charge that the vaccines are unrefined, Mitchell cheerfully pleads guilty. He made a conscious decision in 1984, he says, to make his vaccine much more crude in hopes of stimulating a more vigorous immune response. After testing a number of different melanoma tumors, he selected two that had different properties in terms of growth rate, virulence, and molecular characteristics. He ground them up, tested them in animals to make sure they could not generate new cancers, and then injected them into patients to see if the bits and pieces stimulated an immune reaction.

Perhaps the most persistent criticism of cancer vaccines is a philosophical one. Clinicians like Mitchell, who see cancer patients every day, feel compelled to offer an alternative to patients beyond the reach of standard therapies, even if it appears to work only 20 percent of the time (and for reasons that remain unclear). Basic researchers, often screened from the wrenching tragedy of malignant disease, argue that it's premature to give vaccines to humans. More people will benefit in the long run, they say, from a rigorous study of cancer biology in the laboratory. It is a tricky question, but one that from an individual patient's point of view has a very simple answer: "In the long run" will be too late.

To Mitchell, the main goal has always been to keep the clock ticking. "Duration to me is key," he says. Duration has its own price, though, and Laura Abrams was among the first to discover it.

After her lung metastasis disappeared in 1987, nothing about Laura Abrams's recovery from melanoma seemed remarkable, except that she became able to predict the imminent appearance of an occasional, recurrent tumor because of an allergy-like itching. But in the summer of 1988, she returned from a week-long hiking trip in Yosemite National Park feeling, in a word, funny. She began to have trouble controlling her right hand. She ignored several other symptoms until, one day, she bumped her head on a car door and her entire right side became paralyzed. "And then I knew I had a big problem," she admits. "The glimmer of death--I call it the White Door--was staring me in the face."

Abrams knew-all the survivors know--that if the cancer comes back, it tends to come back in the brain. It makes sense, in a grim sort of way, because the brain is protected from the rest of the body, including the immune system, by a biological filter called the blood-brain barrier. Hospital tests quickly established that Abrams needed emergency brain surgery, which she underwent in August 1988.

There is a photograph from that period of Abrams and a young woman named Gloria Gathers[a]. Gathers was another of Malcolm Mitchell's long-term survivors; she'd started on the vaccine in 1987. In the picture, Abrams is bald from the brain surgery and a brief course of radiation, and Gathers is slyly draping some of her long, dark hair over Abrams's bare head. Among patients struggling for dignity, such small kindnesses are never forgotten.

Gathers was a social worker in Santa Monica whose melanoma had first appeared in her right shoulder in 1982, when she was only 27 years old. She responded well to the vaccine: Three large tumors disappeared, and a fourth was removed surgically. Gathers and Abrams met in the waiting room at Norris. "We became friends," Abrams says, "because we both had a love of traveling."

There is another picture, this one from the 1991 party at Norris, and it shows the two women standing together. Abrams's is the body language of triumph: Jaunty, chin thrust out, she seems almost defiantly healthy. Gathers's body speaks a different, more tentative language. Bowed a little, her smile somehow pinched, she seems visibly unconvinced that she belongs at a party for survivors. In that picture, it was her turn to wear a turban over a hairless head. To the other members of the Melanoma Club, the turban was shorthand for brain mets.

"It came back with a vengeance," Mitchell says, "and almost nothing we did changed the course." Surgeons took care of the first brain tumor, but the melanoma kept popping up elsewhere, in vital organs, the spinal column, the brain again, what doctors refer to as dire sites.

In the spring of 1991, Gathers and Abrams decided to take the trip they had talked about. So in May, they headed off for a week in Maul and a week in Kauai. By that time, Gathers needed to travel by wheelchair. "It was something we always wanted to do," Abrams says, "and we felt we were running out of time."

They went shopping together and lazed on the beach. They talked about every subject under the sun, save one: the future. "One night we were having dinner at the restaurant that overlooks the scene of Bali Hai from the musical South Pacific," she says. "It's right on the water, with the sun going down over the mountains and people singing in the background. We got there early, but we didn't get the table with the best view. I thought to myself, Well, I can come back here and see it another time, but Gloria won't have that chance." Indeed, Gathers deteriorated so rapidly after they returned home that she died before the bills from the trip arrived in the mail barely a month later.

"We're still losing a lot of people," Mitchell admits. "We're still losing the majority of them."

Why is it that only a few patients respond to the vaccines while so many others do not? An answer may come from other quarters, like the Belgian laboratory of immunologist Thierry Boon, at the Ludwig Institute for Cancer Research. Recently, after 20 years of painstaking study, Boon for the first time identified the Holy Grail of tumor immunology: a family of proteins that appear on tumor cells but not on healthy cells, proteins that should set off alarms for the immune system. Unfortunately, not all melanomas display these so-called tumor-specific antigens; even more unfortunately, only a minority of people possess the biochemical makeup that renders these antigens visible to the immune system.

Boon's results may ultimately allow doctors to create more specific vaccines and predict which patients are likely to respond. But the state of the art today is by all accounts more of a shot in the dark, with a lot of misses. "It's just that you know you're making inroads," says Mitchell. "I don't think any of us expects a magic bullet, in the sense that we're going to cure the disease in one swoop. I mean, you're a fool if you believe that. You don't make big strides; you make little steps."

And when fortune smiles on so few, how do they bear the burden of their good fortune? That is the kind of question that haunts Laura Abrams these days. It is still raining; she tugs at a tissue on her lap. "Here I am," she says. "I don't know why I'm here. You feel a little guilty that you're here, and you feel also a little happy."

What you are left with, then, is a few survivors, and what those few survivors are left with are a few too many thoughts. "I wish I had somebody to talk to now who's at my stage, who's starting to have the grimy problems of life," Abrams says. "You gained weight. Your boss sneered at you. You lost your wallet. It's the round peg in the square hole. You look normal, you act normal, but you're not normal." If you ask the ones who have survived--the banker, the jockey, the college president--they will all tell you that Mitchell's "small steps" have carried them a great distance, into richer, more focused, and unexpectedly longer lives. They will also tell you that's not enough, that the problem with the Melanoma Club is that there aren't enough old-timers in it, not enough new members, not enough scientific understanding to explain what made them qualified to join.

"I do feel guilty," Laura Abrams says quietly. "I'm the luckiest person in the world. I don't know why it happened, but it did. I don't know how long it will be this way." There is effort, here, not to look at photographs of the Melanoma Club, not even to scan them in the mind's eye. "I'd like it to happen in everybody." She glances outside at the downpour, and you can see in her eyes that she thinks it is nonetheless an unusually beautiful day.

* This name has been changed.

PHOTO (COLOR): LAURA ABRAMS, EIGHT YEARS AFTER DOCTORS SAID SHE HAD A YEAR TO LIVE

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By STEPHEN S. HALL

Stephen S. Hall is a contributing editor.

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