Made to Order

by Joan O'C. Hamilton

Photography by Glenn Matsumura

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Lymphoma
Rituxan

IN A LOCKED ROOM at the back corner of a campus lab is a rich biological storehouse. Seven superchilled tanks sit, like squat beer kegs, behind the bolted door. Ronald Levy dons gloves and lifts the top off one. A cloud of nitrogen vapor puffs out. He reaches into the tank and retrieves a wedge-shaped rack. In the rack sit hundreds of vials holding patients' tumor cells, a few dating back as far as the 1980s. Some of the patients have long since died, but traces of their cancers live on.

Early in his research career, Levy used samples like these to engineer tumor-attacking monoclonal antibodies, becoming the first to succeed in treating cancer this way. The eventual result: a new class of cancer drug. Today, he uses the samples in another novel treatment he's testing: custom cancer vaccines.

Levy's experimental vaccines, specially prepared from patients' own cancer cells, goad the immune system into recognizing and attacking tumors. Each vaccine is, as he puts it, "literally made to order." So far tried mainly against the incurable blood cancer known as B-cell lymphoma (see box), the vaccines are among a handful of promising treatments to emerge so far from the field of cancer immunology. All pit the body's natural defenses against malignancy.

In his 30 years as a scientist and physician, Levy has seen his strategies against cancer move in and out of favor. Cures remain stubbornly elusive. Yet he's retained the energy of a new recruit while amassing the scars and medals of a veteran.

WHEN LEVY ARRIVED at the National Cancer Institute in 1970, he had narrowly missed serving in two wars. Medical school at Stanford (MD '68), a hospital internship and residency in Boston, and now his nci appointment in Maryland had kept him out of Vietnam. He had also been on a fellowship in Israel during the 1967 Six-Day War and had offered to serve, but he never saw action because he didn't speak Hebrew.

A year into the nci fellowship, his number finally came up. Richard Nixon declared the War on Cancer, and this time Levy not only spoke the language but was already in the trenches.

The mild-tempered, scholarly 29-year-old had joined a band of free-thinking immunologists who rejected the conventions of cancer research. Doctors at the time relied on three brute-force weapons against cancer: surgery, radiation and toxic chemotherapy. More often than not, those approaches failed; sometimes they actually killed the patient. Levy and several other young researchers at nci envisioned a different strategy. The ultimate anticancer tactic, they believed, would exploit the body's own disease-fighting mechanisms, as well as the biology of cancer itself.

With Nixon's 1971 cancer initiative came a surge of funding for such research. This was also the dawn of the biotech revolution. For cancer immunologists, it was a heady era--"a really exciting time with seemingly unlimited resources," Levy recalls. "There was a feeling that great things were just around the corner."

Some important advances were around the corner, along with frustrating detours and dead ends. After three decades, cancer immunology has gained respect, but doctors still talk of remission, not cure. Levy's monoclonal treatment faced a setback when it appeared to fall short of the initial media hype (see box, page 68). It evolved, however, into an established drug, Rituxan, that is improving the outlook for many thousands of patients. And Levy, at 59, has won most of cancer research's highest awards.

The Robert and Helen Summy Professor of Medicine and chief of oncology at Stanford, he's lauded not only for his cutting-edge studies, but also for his ability to translate them into lifesaving treatments. "Dr. Levy is unusual in that he's an excellent basic scientist who understands immunological science and is also a competent clinician who understands the reality of human disease," says emeritus professor Saul Rosenberg, the venerable oncologist who recruited him to the Farm and has always been a mentor.

Having seen Rituxan clear the hurdles to become the first fda-approved monoclonal cancer drug, Levy is now trying to add a second major treatment advance--the custom vaccine--to his list of achievements.

SUZANNE WREN FIRST came to Stanford in 1989, hoping to get into a vaccine trial. Diagnosed a few months earlier with non-Hodgkins B-cell lymphoma, the 41-year-old mother of two flew out from Milwaukee to meet with Levy's team. Against her doctor's advice and the urging of her family, she had not yet begun chemotherapy. She was worried about its side effects and wanted to explore the vaccine prospect first.

A doctor from Levy's group told her he thought she was a good candidate for the trial, but he insisted she begin chemo as soon as she got home, in part because her vaccine would take many months to develop. Wren did start chemotherapy, and she responded well to it. Her tumors did not grow during that time. Nor, unfortunately, did they go away.

Three years passed before her experimental vaccine was ready. She received five injections spaced out over approximately a year. "Within 24 hours of the first shot," Wren recalls, "I was so sore and stiff I was almost immobilized, [as if] every cell in my body knew there was something that shouldn't be there." Then, a day or two after each injection, she'd feel fine again. There was no drop in blood counts, no hair loss or anorexia, none of the dragged-out fatigue for which chemotherapy is notorious.

Gradually, her tumors disappeared, and the cancer has never returned. Her good health has lasted for 12 years now.

Wren says she feels lucky to have been in the study. So does Jama Beasley of Redding, Calif., ringleader of an informal network dubbed "Levy's lymphomaniacs." Beasley first met Levy in 1995 after she'd already completed the injection series and her tumors had diminished. (The shots are frequently given by others on the team.) She was struck by his humility. "When I met him I said, 'Thank you for my life.' Dr. Levy said it remained to be proven how much credit should go to the vaccine and how much to my zest for life."

It's exhilarating to beat the odds against disease, but dramatic testimonials make Levy a little sheepish. For every victory in his studies, he says, there are others who don't respond. Those failures weigh heavily. They are also what drive him forward.

"We are optimistic because we are hoping and expecting to improve the outcome for our patients. But it doesn't always work," he says. "Then we push the limits of our current knowledge and try for better. If we don't keep trying, we will never make advances.

"Amazingly, some patients [whose tumors recur] say they feel they've let us down. They want to know if we will still want to take care of them. Of course we will; we never abandon our patients. And we really don't know what would have happened to them if we hadn't tried our experimental therapies. They may have actually benefited [from the vaccine] to some degree."

A TALL, BESPECTACLED man whose lab coat covers a crisp dress shirt and tie, Levy smiles as he ambles through his large suite of laboratory spaces. The lab is on the ground floor of the Saul A. Rosenberg Cancer Research Center, at the western edge of campus. Levy runs it jointly with his wife, Shoshana Levy, a professor of medicine and respected molecular biologist. Together, the two of them stroll these halls every day, carrying on the tradition of managing a family business. (Ron's parents launched Edwards Luggage Stores more than 50 years ago.) Shoshana turns left to coach students probing cancer biology as Ron turns right to confer with research fellows in immunology and oncology. He describes the operation with a grin and a shrug: "We just run a little mom-and-pop lab."

The two of them met in 1967, when he was a fellow at Israel's Weizmann Institute and she was a grad student working in the same lab. Ron arrived on the eve of the Six-Day War, and the romantic sparks flew right away. The couple volunteered together to help in the war effort and were married within a year. After Ron finished his MD at Stanford, Shoshana completed her PhD at Tufts, continued her research and gave birth to their three daughters, Tali, JD '97, Naomi, ma '98, and Karen, '95. "We do virtually everything together," Ron says.

Karen, now at Berkeley, calls her parents "probably the happiest couple I know." Their successful collaboration still amazes colleagues and students. "I've always wondered what they talk about at night around the table," one lab member confides. "We did have a no-shoptalk rule at dinner," recalls Karen--but business inevitably crept into the home. She recalls one day, for instance, when "I came back and found the entire lab in our hot tub."

A photo of that gathering hangs in the Levy lab today, along with snapshots of Ron and Shoshana biking and windsurfing and dressed as Civil War figures at a costume party. Alongside such mementos are the familiar trappings of scientific research: banks of sinks and stainless-steel instruments; warnings about radioactive wastes and emergency eye-wash showers; coffee cups and bike helmets at the students' stations. There's a "work hard, play hard" ethos about the place.

Under giant sterile hoods in a separate "tissue-culture room," three researchers are hunched over some deadly serious work. They're tinkering with tumor samples to refine the vaccine mixtures that are currently on the lab's front burner.

MOST VACCINES ARE given to healthy people to protect against infections like measles or polio. Cancer vaccines aren't meant to prevent cancer. Instead, their aim is therapeutic.

Still, the underlying strategy is much the same. Vaccines are made from pathogens, or disease-causing substances, that have been inactivated so that they won't harm the body. They spur the immune system to build up defenses against that "enemy," leaving the body alert and armed to attack the real thing.

Here's where a key distinction comes in. When confronted with an infectious invader, the immune system recognizes it and responds vigorously, cranking out naturally produced chemicals and white blood cells to wipe out the enemy. It's not much good, however, at recognizing cancer as an enemy. So a cancer vaccine, in order to work, must trick the immune system into reacting to cancer. Levy achieves this by linking a special protein from tumor cells to other substances, called carriers, that irritate and awaken the immune system, rousing it into "fight" mode. The noxious chemicals turbocharge the body to attack the tagalong tumor protein. "We're trying to retrain the immune system to make an effective response," he says.

The beauty of cancer immunotherapy, conceptually at least, is its selectivity. Chemotherapy and radiation unleash an indiscriminate bludgeoning that damages healthy cells along with the cancerous ones, leaving patients infection-prone and literally feeling poisoned. Vaccination triggers a targeted attack that's more like a fleet of cruise missiles. It stimulates the body to dispatch antibodies and white cells to tumors, which it has "taught" the immune system to seek and destroy.

Taking that concept from bench to bedside has been anything but straightforward, however. While many cancer vaccines have been tried--targeting melanoma and kidney malignancies, among others--only a few seem to prompt tumor regression. Of those, only Levy's are truly tumor-specific, homing in on a protein unique to the patient's cancer cells.

Levy's singleminded focus on lymphoma is what makes this specificity possible. Lymphoma cells feature a biological oddity: on the surface of each sits a "marker" protein distinct to that one patient. The marker is the fundamental ingredient in every vaccine made in the Levy lab. Starting with cells biopsied from a patient's tumor, the researchers isolate the protein, manufacture it in larger quantities and then blend it into the carrier mix. The immune-stimulating carriers might include irritant oils, messenger molecules called cytokines, specialized immune warriors called dendritic cells and/or a large, sticky protein from the blood of a sea limpet. The patient gets five injections, followed by cytokine infusions to keep the immune system on its toes. Levy's team tracks each case closely, measuring immune response and gauging tumor shrinkage or growth.

Fine-tuning the carrier formula has been a long struggle; the lab has tried more than a dozen recipes so far. Isolating and preparing the marker proteins is also extremely laborious. In all, it takes three to six months of work by a team of highly trained experts to produce one person's vaccine.

The key to the vaccine-- its painstaking personalization--has thus been its limiting factor. These vaccines won't see broad use until someone develops a cost-effective way to scale up their production.

Nonetheless, there's a growing list of patients for whom the custom approach appears to be paying off.

LEVY HAS LED a dozen vaccine trials so far, treating about 300 people in all. The trials, funded mainly by the National Cancer Institute and the American Cancer Society, have tested different formulas against advanced-stage, slow-growing b-cell lymphomas. Most participants start out with their tumors already quelled into "first remission" by an initial round of chemotherapy. Without the vaccine, such patients would, on average, relapse within one to three years.

In contrast, about half the people who receive Levy's vaccines mount an immune response against their tumors--something never seen among the unvaccinated. These "immune responders" stay disease-free for an average of six years, compared with 1 1Ž2 years among nonresponders. The figures keep rising as Levy refines his formulas.

He emphasizes, however, that the benefit has yet to be verified. In two new studies crucial to the future development of the treatment, the National Cancer Institute and a start-up called Genitope are trying to tease out cause and effect among patients who seem to respond favorably to vaccination. The uncertainty arises because some people with slow-growing lymphoma have a significant remission after the first round of chemotherapy, with or without vaccination. The seeming recovery might even last 10 or 12 years, but each remission becomes shorter until the patient dies.

Could that remission phenomenon account for some of the improvements seen in Levy's small trials? Is the vaccine itself prompting tumor shrinkage and sustaining remissions, or is it coincident with something else going on with the patient? These are the questions that need to be answered.

Genitope, a Redwood City-based company launched in 1996 by Dan Denney, PhD '90, has started a randomized, double-blind study of 400 lymphoma patients nationwide. Two-thirds will receive chemotherapy plus the vaccine series; the rest will receive only chemotherapy. (The NCI study, though slightly smaller, is taking a similar approach.) Researchers will follow each patient for at least four years and then compare outcomes in the two groups. The first interim results should be ready for evaluation in 2003.

The trial is expensive, and it's no coincidence that the work is being financed and pushed by a gutsy biotech start-up and not a major pharmaceutical company. "Big Pharma will never invest in this," Levy says with the stoic acceptance of one who's spent his career looking for research funding. With a custom therapy like this, large-scale production is the biggest worry, he says. "There's the question of whether you can make, technically and commercially, a custom approach [for a large market]," Levy explains. Furthermore, "the FDA does not like customized therapies. They're hard to regulate [because each is different]."

Genitope hopes to overcome the production hurdle with a technology conceived by Denney. The idea is to speed and standardize vaccine preparation while retaining customization--specifically, by using genetic engineering to clone and isolate the genes encoding the crucial marker protein and "express" them in a standardized tissue-culture system. If it works, Denney asserts, "we can knock out custom pharmaceuticals the way Michael Dell knocks out custom computers."

Other manufacturing strategies now under study use bacteria, hybrid tumors and insect cells to churn out the product. One intriguing approach, under development at Large Scale Biology in Vacaville, Calif., uses genetic engineering to trick tobacco plants into making large quantities of custom vaccines. As Levy notes, there's "a satisfying irony" in using tobacco to fight cancer.

WHILE COMPANIES PURSUE scale-up techniques, those little vials of cancer cells keep chilling in their tanks. They grow more valuable every year.

With the recent explosion in human genome research, this has become a rare and precious cache: live, carefully archived genetic material from scores of cancer patients whose every medical up and down has been recorded over time. Levy's team has kept precise accounts of how each patient fared--whether the vaccine seemed to fire up the immune system, whether the tumors ever came back, how long the person lived after treatment. "Nobody knew when they started saving these how valuable they'd become for genetic analysis," says John Timmerman, a research fellow in the Levy lab.

With such a record, mysterious failures suddenly have the potential to become the stuff of breakthrough science. John Stevens, MD '87, the American Cancer Society's vice president for research, calls the tumor trove "one of the most valuable biological storehouses in modern cancer research." Someday, these archived genes may reveal why Suzanne Wren's body took up arms against her tumors while other patients responded sluggishly. Already, Levy is collaborating with geneticists--analyzing the genes of tumor cells and comparing them with patient outcomes--to "type" more precisely the subtle variations of lymphoma and further tailor the treatments for each.

For cancer researchers, the newly decoded human genome "is like what a dictionary is to a writer," says Levy. "It ratchets up what we're able to do. It has made a lot of previous work obsolete. It sharpens our ability to diagnose cancer and make distinctions between different patients' tumors that we once thought were the same."

He speaks softly, but the intensity comes through. "When I was an intern," he says, "I had the feeling everything [in cancer research] would be done by the time I finished my internship. Yet it's still exciting to this day. Cancer is a big problem, a fascinating problem--that hasn't changed. There's always something happening that we couldn't have imagined in the past. And you always feel as if you're about to make the next breakthrough."

Joan O'C. Hamilton, '83, covers the biotech industry for Business Week and is a frequent contributor to STANFORD.

Lymphoma: Insidious, Increasing

JAMA BEASLEY OF Redding, Calif., was busy running a business in the early 1990s when she started feeling ill. The 45-year-old was tired most of the time, had a lingering, low-grade fever and suffered frequent night sweats. Menopause, her local doctors kept telling her, and they gave her hormone therapy. But the symptoms persisted. After seeing six physicians in one year, she was finally referred to a psychiatrist.

It took an mri scan for a separate back ailment to reveal what the other symptoms meant. The scan showed a mass the size of a volleyball in her abdomen, which doctors at Stanford later diagnosed as B-cell lymphoma. "The tumor was so big it was like a child in there," recalls Beasley, who has been disease-free in the six years since she received chemotherapy followed by Levy's vaccine.

B-cell lymphoma is Levy's nemesis, the incurable cancer to which he has devoted his career. It's the most common of the malignancies known as non-Hodgkin's lymphomas, which together represent the nation's sixth leading cancer diagnosis. While some other cancers have declined in recent decades, non-Hodgkin's lymphomas have mysteriously increased, with new cases rising by 75 percent over the past 20 years, according to the National Cancer Institute. (Pesticide exposure is among the suspects; one sure factor is aids.) Approximately 250,000 Americans currently have this disease, and some 62,000 new cases turn up each year.

All lymphomas are cancers of the lymphatic system--the network of tissues, organs and vessels that sends infection-fighting white blood cells coursing through the body. The malignancies can arise practically anywhere in the body, eventually filling lymph nodes with proliferating cells that become firm tumors. Often, patients don't feel any tumors. Instead, like Beasley, they experience general malaise, including exhaustion, low fever and persistent night sweats.

So far, researchers have delineated about 35 types of non-Hodgkin's lymphomas. These are categorized by the rate of cell proliferation, the developmental stage at which the cells first went haywire, and the kind of cell involved (B versus T lymphocytes). When white cells turn malignant at a very early stage, they can become leukemia, a close relative of lymphoma.

Ironically, faster-growing, "aggressive" lymphomas respond relatively well to chemotherapy, with about 40 percent of patients experiencing remissions lasting five to 10 years. But most participants in Levy's trials have slow-growing tumors of advanced-stage B cells. With such "indolent" malignancies, the outlook is murkier. Tumors might vanish for years after chemotherapy--occasionally even for a decade--but they inevitably return at an accelerating pace. Most such patients die within 10 years of diagnosis.

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Rituxan: Hope and Hype

TO MANY IN BIOMEDICAL research, the name Ron Levy is synonymous with one of the earliest cancer immunotherapies: tumor-attacking monoclonal antibodies. Indeed, if his vaccine work pays off, it will hurtle him into the scientific spotlight for the second time in his career.

As far back as 1975, when he joined the Stanford faculty, Levy was convinced that the key to defeating lymphoma lay in exploiting a "marker" protein unique to each patient's tumor cells. He envisioned two possible ways to do this. One was to create a custom vaccine--the work he is doing today. The other involved a brand-new lab technique, pioneered in England, in which researchers use mice to manufacture large quantities of antibodies genetically engineered to go after a single target. These are monoclonal antibodies.

As the 1980s dawned, Levy's team was making monoclonal antibodies to home in on the tumor markers of individual patients. The idea was to inject them as a highly selective, customized drug. The antibodies would ignore healthy cells, attacking only the cancer.

Then along came a patient who seemed a good candidate for either approach. Phil Karr was a retired engineer who had been treated at Stanford for several years. By 1980, his condition had deteriorated dramatically. Levy had samples of Karr's lymphoma cells, and after wrestling with himself over whether to try a vaccine or the monoclonal antibodies, he chose the antibodies.

Bingo. The results seemed miraculous. Within a month, Karr's tumors shrank and his energy returned. X-rays showed no traces of cancer. When the results came out in the New England Journal of Medicine, they set off fireworks. Journalists seized on the "magic bullet" metaphor. Venture capitalists rushed to launch companies to capitalize on the findings. "It helped start the biotech industry," Levy says. Karr's dramatic improvement led many to believe that a cure for all cancers was at hand.

What happened next has become an all-too-familiar scenario in the high-stakes biotech biz. Almost immediately it was clear that other research teams were not getting the same great results. Their monoclonal antibodies weren't attaching to the right targets and were prompting rejections in many patients. Making the antibodies was expensive and time-consuming, and scientists had difficulty attaching them to chemotherapy drugs and radioactive compounds. Expectations surrounding the new treatment plunged, as did the stock prices of companies formed to pursue it.

No one ever questioned Levy's findings or integrity. Still, rumors circulated that his "miracle cure" had been a fluke and even that the patient had died. Phil Karr is, in fact, alive and well, living in Southern California at age 87. And while other researchers had trouble replicating that success, many subsequent patients in the Levy lab responded well to the treatment. "We did it 50 more times," says Levy. "Three-quarters of the patients had significant remissions, and in five or six people the tumors never returned."

"It wasn't difficult for us to duplicate the remissions," recalls David Maloney, MD '85, PhD '91, a member of Levy's lab at the time and now an associate professor at the University of Washington. "But there was huge hype based on the successes we had. Others rushed in and tried the wrong targets, and it didn't work."

In the initial financial flurry set off by the Karr case, Levy and a former postdoc from his lab launched a company, IDEC Pharmaceuticals, to commercialize the new treatment. After several years of effort, idec found it couldn't make the custom antibodies efficiently enough to sell like a conventional drug. So idec changed course, making monoclonal antibodies against another, more common marker on B cells--no longer tumor-specific or unique to individual patients but far more efficient to make. Levy helped test the product, although he had divested himself of all holdings. IDEC and partner Genentech finally won fda approval to market it in 1997. Studies showed that the drug, Rituxan, shrank tumors by 50 percent or more in about half of all patients who received it.

After all the hype and the backlash, Rituxan became the first new treatment approved for lymphoma in two decades and the first monoclonal-antibody cancer drug cleared by the FDA. "Ron created a whole new paradigm for cancer therapy," American Cancer Society vice president John Stevens says. "If he were remembered for nothing else, that would be sufficient for most careers."

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