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An Idea Is Planted: Firm Uses Tobacco to Grow Cancer Drugs

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Times Staff Writer

The tobacco seedlings reaching toward the bright sunlamps in an indoor greenhouse look fairly ordinary. But the young plants growing in this rural nursery aren’t destined to become cigarettes.

Inside their broad, green leaves, the plants are pumping out bits of cancer tumor as they spread upward in the 80-degree warmth. In a laboratory nearby, the tumor fragments will be wrung from harvested plants and used to make an experimental biotechnology vaccine.

So far, 16 people with non-Hodgkin’s lymphoma, an incurable cancer of the lymphatic system, have received this vaccine produced by Large Scale Biology Corp. One patient was a 29-year-old mother of two; another was a 12-year-old boy. Each received a vaccine that was not mass-produced but customized to attack his or her specific tumor, a step toward the long-promised era of “personalized medicine.”

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Lymphoma spreads slowly, so it will be years before anyone can be sure that the vaccine works. But the early signs are encouraging. At a medical conference in Philadelphia last week, Large Scale Biology reported that 10 of the 16 patients made tumor-fighting white blood cells after getting the shots, a large percentage for a cancer drug.

Much is riding on Large Scale’s vaccines -- both for cancer patients and for the company.

After raising $89 million from an initial public stock offering in 2000, Large Scale has 12 to 18 months of cash remaining. The cancer vaccine is one of two drugs the company is feverishly developing. And with its shares hovering in penny-stock territory, time is running out for the company -- though it wouldn’t be the first biotech firm to roar back from the edge.

All current biotechnology drugs approved by the Food and Drug Administration are made by gene-splicing bits of DNA with live cells -- usually hamster cells -- and turning them into mini-cell factories to produce a specific drug. But Large Scale’s scientists believe that a vaccine created through plants might be purer and avoid copying defects found in mammals. Large Scale chose tobacco because it is cheap and grows rapidly, a promising vehicle for producing many small batches of vaccine at an acceptable price.

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Next month, Large Scale hopes to persuade the FDA to approve a more elaborate human test of its lymphoma vaccine on 280 patients. Yet even if the company gets that go-ahead, it must raise an additional $50 million to fund the trials, which could take four years to complete.

The founder of Large Scale is 48-year-old Robert L. Erwin, an earnest, rail-thin biologist with a very personal grudge against cancer: It killed his first wife in 1994 after agonizing surgeries, radiation treatments and chemotherapy.

From the window of his Vacaville office at Large Scale, Erwin can see the sprawling $500-million factory where South San Francisco-based Genentech Inc., the world’s second-largest biotechnology company, makes its breast cancer drug Herceptin. The drug combats breast cancer cells and might have saved his wife, Marti, but she died while it was in development.

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The loss of his wife drove Erwin to find a way to slash development times for cancer medications to weeks instead of years. Large Scale says it now can develop a vaccine for a patient in six weeks and hopes to eventually produce enough custom vaccine to treat 10,000 patients each year.

“One thing I’ve learned,” said Erwin, “is that speed is important for some patients.”

The vaccines produced by Large Scale differ from shots given to healthy children to protect them from measles or chicken pox. People who get a lymphoma vaccine already are sick, in part because their immune systems failed to notice or sufficiently fight their tumors.

There are more than 50 biotech vaccines in development against various types of cancers, but none has reached the market and few are custom-made for individual patients. Typical is a melanoma vaccine being tested by CancerVax Corp. of Carlsbad, Calif., that contains 30 different tumor fragments commonly present in skin cancer.

Many scientists believe that lymphoma requires a personalized approach because it has substances on the surfaces of its deadly cells that vary from patient to patient. A vaccine made from these so-called surface antigens could train a patient’s immune system to recognize and fight the cancer, researchers believe.

Large Scale teamed up with Stanford University scientist Ronald Levy, who started work on lymphoma vaccines in the late 1980s and who now runs the firm’s first round of drug trials.

Levy and his students have treated hundreds of patients in his Stanford laboratory over the last two decades. A former student, Larry W. Kwak of the National Cancer Institute, is now a rival and is preparing to test a personalized vaccine on hundreds of patients in a clinical trial that could lead to FDA approval.

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To this point, Large Scale, in keeping with standard practices, is providing its cancer vaccine for free as the company conducts its testing, and no one knows what this kind of treatment might really cost in the end.

Kwak figures it could be as much as $50,000 for a series of five or six shots. That would be half the $100,000 cost of a bone-marrow transplant -- a last resort for lymphoma patients -- but 10 times the expense of standard chemotherapy. Still, insurers may be willing to cover vaccines if the shots allow patients to avoid years of expensive medical care, Kwak said.

Large Scale believes that it can shave costs by producing drugs in tobacco, an innovative counterpoint to Kwak’s complicated but time-honored technique that involves fusing a patient’s tumor cell with a mouse antibody. Large Scale’s president, John D. Fowler, said the company’s production expenses could be 30% lower than those of biotech firms that use the routine method of making drugs in rodent cells.

Large Scale uses a natural enemy of tobacco, the tobacco mosaic virus, to produce its vaccine. The company slips genes from a patient’s tumor into copies of the virus, a virulent bug that is a scourge to farmers.

As the altered virus infects plants, it produces tiny tumor fragments that build up in the tobacco leaves and stems. Six weeks later, the plants are harvested, washed and spun in a centrifuge to extract plant juices. The solution is purified and reduced to an amount of vaccine that wouldn’t fill a Coke can. Patients receive six shots spread over as many months along with other injections to boost the immune system.

In the company’s greenhouse, young plants with yellowing, mottled leaves grow in neat rows on long, wooden tables. The plants are a cousin of the tobacco strain grown for commercial use. A team of horticulturists tends the plants, which are grown from seeds no larger than a pinhead in temperatures that never dip below 72 degrees.

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Lab assistants painstakingly infect the plants by hand, gently scratching the leaves with a solution containing the virus, which can be transmitted only by direct contact. It takes 1,000 plants grown to a height of 6 inches or so to make enough vaccine for a single patient, an amount equal to half a teaspoon.

Catherine Gallegos, a school administrator in Monterrey County, became one of the first patients to receive Large Scale’s vaccine in May 2001. By then, a harsh chemotherapy regimen had forced her neck and abdominal tumors into remission, but doctors warned that the cancer probably would recur.

Gallegos’ shots ended a year ago, but her immune system continues to make anti-tumor white blood cells. To Gallegos, the vaccine offers a chance to break the inevitable cycle of chemotherapy treatments followed by shorter and shorter remissions, the deadly hallmark of lymphoma.

“It gives me peace of mind to know that my system is responding,” said Gallegos, 57, who lives near Santa Cruz. “I feel like I have my life back.”

Erwin didn’t have cancer vaccines in mind in 1986 when he founded the predecessor of Large Scale. But his first wife’s illness sharpened his business focus. After the standard artillery of surgery, chemotherapy and radiation failed Marti, Erwin became convinced that a different approach was needed.

Marti’s inability to obtain Genentech’s experimental drug also transformed Erwin into a crusader, an unlikely role for a biotech CEO. With his blessing, fellow activists stormed Genentech’s campus after her death in a mock funeral procession. Since then, Erwin has quietly lobbied pharmaceutical companies to provide experimental medications to patients whose cancer defies treatment.

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Erwin acknowledges that it can be difficult to balance his zeal with his responsibilities as Large Scale’s CEO. His company recently was ready to provide the cancer vaccine to an additional patient, who didn’t technically qualify for the drug trial, but she did not survive a bone marrow transplant. However, Large Scale’s financial condition doesn’t allow it to routinely offer treatment to others.

In the next few months, if the firm does not find a partner to fund another round of cancer vaccine trials, the vaccine could be set aside. But it probably wouldn’t sit on a shelf permanently. The company hopes it can license its technology or possibly try to develop it again later.

“It isn’t just about making money,” Erwin said. “We’re giving patients something that really matters.”

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