In 1993 [Introgene], [Crucell]'s predecessor,  was established as a spin-off of Leiden University. The company formed a partnership with Genzyme to collaborate on its vector technology and viral-based products. In 1999 the company founded [Galapagos Genomics (renamed by 2005 to Galapagos NV )] as a joint venture together with [Tibotec]. In 2000 [Introgene] acquired U-Bisys to form [Crucell].

In 2006, [Crucell] and Swiss Berna Biotech; Swedish SBL Vaccines and US-based Berna Products joined forces to become the sixth largest vaccine company worldwide, with their own clinical programs.[citation needed]

On 7 January 2009 [Crucell] released a press release saying Crucell and Wyeth were in discussion on a merger of the two companies. On 26 January 2009 Crucell released another press release saying the discussions on a combination of Crucell and Wyeth was discontinued due to Pfizer's acquisition of Wyeth.[citation needed]

In September 2009 Johnson & Johnson bought 18% stake in [Crucell] for €302 million in order to collaborate on the development of a flu vaccine.[1] This followed Crucell's discovery of CR6261, a potent human antibody that neutralizes a broad range of influenza A viruses. J&J acquired the rest of the company in October 2010, taking its stake to over 95% by February 2011[2][3] and delisting the company from stock exchanges two months later.[4]

After the takeover by Johnson & Johnson in 2011, Crucell was assigned to Janssen Pharmaceuticals division. In 2014, the subsidiary was renamed from [Crucell] to Janssen Vaccines.[5][6]

[...]

lntroGene

• Wassenaarseweg 72, 2333 AL Leiden, The Netherlands

• [...]

• E-mail: info@introgene.com

• CEO: Professor [Domenico "Dinko" Valerio (born 1956)]

• Contact: J. Boesen, PhD, Manager Business Development

Corporate Overview

lntroGene as founded in June 1993. The company is involved in the research and development of gene therapy technologies and products.( Belgium) headed by Dr Desire Collen. To support the collaboration with the Center of Transgene Technology and Gene Therapy at the University of Leuven, the company incorporated a Belgian subsidiary, IntroGene NV, located in Leuven (Louvain). In. March 1997, the company moved into new corporate facilities, located on the premises of Leiden University in Leiden's Bioscienc Park. The company has a staff of fifty-two, seventeen of whom have PhDs and/or MD degree qualifications.

Financials

ln early 1999, the company completed a $26 million private funding which brings a total of $48 million in four private placements since 1993. These funds will provide IntroGene with the resources required to support its research programs in therapeutic angiogenesis and prevention of restenosis after angioplasty. It will also finance the establishment of a GMP manufacturing plant for the production of gene therapy products utilizing lntroGene's PER.C6 adenoviral production line.

Technologies

lntroGene's main focus is on gene therapies involving hemopoietic stem cells, and viral vector development.

1. The PER.C6 [TM]

   1. • A significant milestone has been achieved by IntroGene with the launch of the PER.C6 adenoviral packaging cell line which is a safe manufacturing sy·stemfo r adenoviralg ene therapy products. The PER.C6 cell line was generated after immortalization, of primary human cells with an E1-mini gene of a human adenovirus. As the E1-sequences present in the PER.C6 cells do not overlap with the E1-deleted adenoviral vector, generation of RCA due to homologous recombination is excluded. Features and benefits of PER.C6 are :

        • 1. Fully characterized packaging cell line for adenoviral vector production

          2. Free of wild-type virus and contaminating vectors

          3. Scalable serum-free suspension system

          4. High cell densities ( > 5 x 10^6 cells / ml ) and yields ( > 1 x 10^11 particles / ml )

          5. High transfectability

      • Using PER.C6 will enable companies, for the first time, to undertake large-scale production of adenoviral vectors free of contaminating replication competent adenovirus. PER.C6 is available for commercialization with collaborative partners.

2. AdApt [TM]

   1. • This adenoviral shuttle vector is available for research purposes only.

Patents

The company currently has applications for fourteen different families of patents surrounding their core technology and manufacturing capabilities. In addition, exclusive licenses are held for a number of significant therapeutic genes, which lntroGene is in the process of commercializing.

Collaborations (academic)

Main collaboration since 1994 is with the University of Leiden, the Netherlands. The collaboration was formalized in 1997 and focuses on basic and applied research into stem cell transduction and viral vectors. In addition, IntroGene has also built up an extensive network of scientific alliances with internationally renowned researchers to ensure that it remains at the forefront of major technological advances in gene therapy. The company has alliances with Rotterdam University Hospital, TNO Primate Center, Leiden University and the Center for Transgene Technology and Gene therapy, Leuven University. In 1997, lntrogene signed a 4-year deal with Flanders lnteruniversity Institute for Biotechnology (VIB) in Belgium to develop gene therapy for cardiovascular disorders. The research will use lntrogene's adenoviral and AAV gene transfer technology and will be conducted under the direction of Professor Desire Collen of the Center for Molecular and Vascular Biology of the University of Leuven and VIB's center for Transgene Technology and Gene Therapy.  lntrogene will have exclusive worldwide rights to all commercial applications arising from the research in the areas of restenosis, arrhythmia, heart failure and pulmonary hypertension using adenoviral, adeno-associated viral and nonviral vectors. One of the lead programs will involve work on the adenoviral transfer of three genes: ceNOS (nitric oxide synthase), PAI-1(plasminogen activator inhibitor type 1) and HSV-tk for the prevention of arterial restenosis.

Corporate Collaborations

lntroGene has entered into several corporate alliances:

• With Genzyme for the development of a gene therapy product for Gaucher's disease.

• There is a strategic collaboration with Boehringer lngelheim for the development of AAV and stem cell technology.

• With JRH Biosciences for co-marketing of PER.C6.

• Other alliances based on PER.C6 include those with Merck, Rhone-Poulenc-Rorer, GlaxoWellcome, Schering, Genzyme, and CobraTherapeutics.

• In May 1999, lntroGene signed a licensing agreement with SyStemix Inc. (a subsidiary of Novartis). SyStemix will license lntroGene's PER.C6 adenoviral packaging cell line in exchange for undisclosed up-front fees, annual payments and royalties on sales of adenoviral gene therapy products arising from the agreement.

• In April 1999, lntroGene BV and Tibotec NV formed a high-throughput functional genomics company, Galapagos Genomics NV. The new company will focus on the rapid identification of human gene functions utilizing lntroGene's adenoviral technology in combination with Tibotec's high-throughput screening capabilities. Galapagos, based in Mechelen, Belgium, will be equally funded by both lntroGene and Tibotec as a joint venture.

Products

Those relevant to gene therapy are:

• For its Adenoviral technology the company's adenoviral HSV Thymidine Kinase gene is a promising therapeutic for the treatment of diseases in which targeted cell destruction is crucial. Examples of such diseases are the treatment of brain tumors, restenosis and rheumatoid arthritis. lntroGene's clinical program consists of phase one clinical studies in patients with glioma ( IGN-HSVtk-GL-06 ) and leptomeningeal metastases ( IGN-HSVtk-LM-06 ). The company also has an extensive preclinical trial program for the treatment of restenosis and rheumatoid arthritis.

• lntroGene's stem cell technology clinical program involves exploring the use of the multiple drug resistance (MDR) gene in the following patient groups: non-Hodgkin's lymphoma, metastatic breast carcinoma and metastatic refractory bladder carcinomas. Also as part of the company's research in to Gaucher's disease pilot clinical trials, to improve the transduction rate of hematopoietic stem cells, using leukemia patients are being carried out.

• IntroGene has an extensive program focusing on the use of adenoviral vectors to deliver the gene for IL-3. This product has the potential to treat a broad spectrum of clinical indications. lntroGene has already carried out preclinical trials which have shown significant tumor reduction when compared to the action of Melphalan in the same animal model. In addition, it was demonstrated with IL-3 that tumor regression occurred in established tumors at sites away from the site of treatment. This program is a key component of lntroGene's research program and is being extended to identify additional tumors that will also show this high degree of sensitivity towards adenoviraI lL -3 gene therapy.

Ever since scientists learned over a decade ago that cancer is the result of defective genes, they have dreamed of shutting down tumor growth simply by replacing the bad genes with good ones.

Researchers at two biotech companies and a pharmaceutical giant believe they are close to making that dream come true, at least for some patients.

In two weeks, scientists will present results of several studies showing, for the first time, that cancer growth in severely sick patients can be stalled through an innovative method of repairing damaged genes. If the initial studies of this "cancer gene therapy" in about a hundred patients hold up, one of the companies, closely held Introgen Therapeutics Inc. of Austin, Texas, believes its technique may be available to doctors in two years.

"We're racing as fast as we can to prove our method works," says David Nance, chief executive of Introgen, which is working with M.D. Anderson Cancer Center in Houston. "If all continues to go well, we think we will be the first on the market with a cancer gene-therapy product. We're aiming for the year 2000."

The technique is based on the knowledge that altered genes play a pivotal role in the underlying mechanism of much disease. But gene therapy is a highly controversial and much-criticized idea. Many drug makers believe it can't be done in large enough doses to work or that it can't work without causing toxic side effects. Hence, the very first human tests to, quite literally, repair the broken genes that drive cancer growth are being watched closely.

"Until recently, I thought gene therapy was science fiction, something to fantasize about. Maybe it isn't," says Bert Vogelstein, a top cancer-gene scientist at Johns Hopkins Oncology Center in Baltimore, who isn't involved in the gene-therapy studies. The three separate trials are being conducted by Introgen, Schering-Plough Corp. and Onyx Pharmaceuticals, a California biotech company.

Jack Roth, an M.D. Anderson doctor who is spearheading Introgen's trials and helped found the company, says initial human tests are aimed at trying to "prove the principle -- that it's possible to stop tumor growth cold, perhaps even destroy the tumors totally, by injecting them with a tumor-suppressing gene." Combined, the trials have involved only a few hundred patients, and gene therapy countered cancer in only a small portion. Still, Dr. Roth is "encouraged by our very first efforts."

Introgen and the others are exploiting a discovery made in the late 1980s about a "suicide gene" called p53. It plays a critical role in controlling normal cell growth. When cells divide, p53 makes certain that all the genes are reproduced accurately. If there are errors in the genes' structure, p53 literally halts the cell-dividing process until the mistakes can be fixed--or forces the flawed cell to kill itself off.

But if p53 itself is damaged -- perhaps by smoking, excessive sunlight or toxic-chemical exposure -- the errant cells divide furiously until they become a tumor.

In the early 1990s, Dr. Roth and others witnessed test-tube experiments showing that inserting p53 into cancer cells stopped the dangerous dividing process. Vowing to try this approach in people, Dr. Roth, whose specialty is treating cancers of the head and neck area, borrowed techniques from scientists who inserted genes into modified viruses to try to fix inherited diseases such as cystic fibrosis.

Animal tests completed in 1996 showed that a modified virus carrying the p53 gene could significantly halt tumor growth and sometimes eliminate the tumor. Last year, Introgen completed Phase I safety tests in 94 patients. The tests were also designed to test the principle of whether p53 could penetrate the tumor and begin restraining cell growth -- and it did. Tumor growth was stalled outright or reversed in 10 patients who had failed to respond to any previous cancer treatments. And in two patients diagnosed as terminally ill, tumor growth halted and hasn't resumed for more than a year.

Introgen, whose research is backed by France's Rhone-Poulenc SA, now is doing efficacy trials in about 100 patients with a variety of tumors. So is Schering-Plough, in separate tests. Researchers hope to expand those tests in the final Phase III trials next year, combining gene therapy with traditional chemotherapy.

WASHINGTON -- In their attempt to understand whether gene therapy is truly safe, some congressional and federal officials are wondering whether other patients -- besides Jesse Gelsinger -- could have died from the experimental procedure.

While top gene-therapy experts' working assumption is that the Arizona teenager was indeed the first to die, they concede they can't be certain. Researchers indicated some deaths were "possibly" related to the gene therapy itself, as opposed to a patient's underlying disease.

For example, Introgen Therapeutics Inc., of Houston, reported to the National Institutes of Health that in one study two deaths couldn't conclusively be explained, leaving open the "possibility" they were related to the gene therapy itself. However, in the final analysis, the company has "very little concern that the gene therapy could have been involved," an Introgen official said.

Patients in gene-therapy trials usually have life-threatening, often terminal illnesses. "Patients in those trials die," Jay Siegel, a U.S. Food and Drug Administration official, told a Senate hearing this week. "And it is usually not possible to make a definitive determination" about the cause of death.

"It may well appear that the death is due to progression of the cancer," he added. "But one cannot make definitive determination as to whether the therapy may in some way have increased that likelihood."

At the hearing, Sen. Bill Frist (R., Tenn.) grilled regulators about whether there were more deaths related to the gene therapy itself among the 4,000 or so participants in the experiments. Since Mr. Gelsinger's death in September, the scientific field has been engaged in a wide-ranging review of its past experiments, and researchers have swamped the NIH with reports about any "adverse events" -- including death -- among study participants.

The Introgen experiment shows how difficult it is to always make a concrete call about cause of death. About three years ago, in one of the company's trials that introduced genes into the body to attack cancer cells, a patient received five doses of a conventional chemotherapy drug as well as the gene therapy. Two days after his last dose of the gene therapy, the patient went to the emergency room, complaining of shortness of breath, the company said. He died 30 days later, and "in the investigator's opinion [the lung problems] ... could possibly be related to study treatment." An autopsy wasn't performed, NIH records show.

"The point is, the patient had worsening disease and a worsening chest X-ray, and this was in the general area the treatment was being administered," said James A. Merritt, vice president of clinical affairs for Introgen, who also noted that all the participants were seriously ill cancer patients. "You cannot exclude that there may have been some contribution to his shortness of breath, the complication he had immediately prior to death."

A second patient in the study died 19 days after his only dose of the gene therapy. The cause of death was unknown, and no autopsy was performed, Dr. Merritt said. The researchers suspected the man's cancer killed him, although complications "possibly related to [the gene transfer] cannot be ruled out," they reported to the NIH.

"Essentially, there was no way to establish a cause of death," Dr. Merritt said. While there was "absolutely no information in the record that would lead us to suspect it was the drug, it had to be included as a possible cause," he said.

Likewise, researchers at Beth Israel Deaconess Medical Center in Boston indicated that two study deaths were "possibly" related to gene therapy, although they ultimately concluded there was "no evidence" to link the gene therapy to the deaths. Essentially, the center said participants were so sick that it became difficult to tell what caused their deaths. The hospital said it needed to change its study design "to enroll healthier patients so they could determine whether adverse events were related to the gene or to the health of the patient."

Even with the ambiguity, gene-therapy experts say the experiments have been generally safe, although they say limits should be set on the use of some types of therapy on certain patients. "There have been toxicities, there have been adverse events," said Inder Verma, a leading researcher. But the only death so far that has been directly linked to the gene therapy, he said, is Jesse Gelsinger's.

WASHINGTON -- An influential Democratic congressman blasted "inexplicable noncompliance" among gene-therapy researchers and criticized the National Institutes of Health for failing to aggressively investigate problems in the field.

In a letter to the NIH, Rep. Henry Waxman of California rapped researchers for not promptly reporting gene-therapy problems to the agency, and pointed to a handful of cases that he said demonstrate other problems involving gene-therapy experiments. In one trial, for example, 38 of the 48 patients died. But, he said, it didn't appear that the NIH conducted an adequate follow-up investigation.

The NIH took issue with Rep. Waxman's criticism. A spokesman said the agency has reviewed "in great detail" hundreds of so-called adverse-event reports from the experiments "and has found nothing amiss."

In addition, the company that conducted the study, Introgen Therapeutics Inc. of Houston, said the deaths resulted from the patients' underlying diseases, not the gene therapy itself. "They had endstage cancer," said James Merritt, Introgen's vice president of clinical affairs. The company said the letter and Mr. Waxman's interpretation of the adverse-event data illustrate the "political circus" now surrounding the gene-therapy field.

Mr. Waxman questioned the thoroughness of the NIH's investigation of the experiment, saying in the letter to NIH's acting director, Ruth Kirschstein, "It would seem obvious that there would be vigorous and immediate oversight of any protocol that results in the deaths of 75% of the participating patients."

In recent months, the gene-therapy field has been rocked by an Arizona teenager's death during an experiment and disclosures that many researchers weren't properly notifying federal officials of safety data from their studies. Mr. Waxman's office reviewed hundreds of pages of adverse-event reports from experiments conducted around the country and submitted to the NIH.

A second experiment singled out by Mr. Waxman involved the University of Pennsylvania in Philadelphia. For one study, Penn promised to send the NIH a follow-up report about a patient's death, but the congressional review of NIH documents didn't show that such a follow-up was sent, Mr. Waxman said. In response, a Penn spokesman said the death occurred more than two years after the therapy and wasn't related to the experiment.

The NIH spokesman said the two experiments cited by Mr. Waxman in which patients died had been reviewed by a special NIH committee, which "found nothing to indicate these deaths were related to gene therapy."

In a third case noted by Mr. Waxman, the wrong drug was administered in a trial sponsored by the NIH and held at Georgetown University Medical Center in Washington. Georgetown said no patient suffered ill effects and that the hospital has changed its pharmacy procedures to prevent additional drug mix-ups.

In the summer of 1997, Patricia Aneff's lung tumor seemed invincible. It had nasty tentacles that made surgery out of the question. Three rounds of chemotherapy "made me look like E.T. but didn't do zippo to the tumor," says the Abilene, Texas, woman. "I didn't think I would live to see the millennium."

Then Ms. Aneff became a test subject in an entirely new way to attack cancer: gene therapy. A lab test found her tumor cells had defective genes known as p53, whose function is to brake runaway cell growth. When doctors injected her tumor with sound copies of p53, it shrank into a little ball, and surgeons handily removed it. Mrs. Aneff celebrated New Year's Eve with friends and then headed to a midnight church service. She now appears to be cancer-free.

Gene therapy seeks to treat diseases by using biological sleight-of-hand to insert replacement genes into cells that have missing or defective copies of those genes. It has come under heavy scrutiny since the November death of 18-year-old Jesse Gelsinger, who had a genetic liver disease, in a trial at the University of Pennsylvania.

Critics note that gene therapy has now been tried for a decade with few positive results. In trial after trial, scientists have injected genes to treat diseases such as cystic fibrosis, only to find nothing happened, probably because the genes never got into cells where they were needed.

Small Successes

But just as public opinion on gene therapy has soured, several significant successes have been achieved. In preliminary trials at Children's Hospital in Philadelphia, children with hemophilia were treated with genes that helped their bodies make a blood-clotting protein they lacked. Boston researchers have relieved chest pain caused by clogged arteries by injecting hearts with genes that caused new blood vessels to grow. And French doctors recently reported initial successes in treating children with a rare genetic defect that destroys their immune systems and forces them to live in isolation.

Only in cancer, however, has gene-replacement therapy progressed into Phase III trials, the final-stage research aimed at getting Food and Drug Administration approval. Pharmaceutical companies Schering-Plough Corp. and Aventis SA, which is working with closely held Introgen Therapeutics Inc., were so impressed with early results that they recently launched large studies in ovarian and head-and-neck cancers.

It is by no means certain the trials will succeed. Scientists fear that gene therapy may kill only those cancer cells in the small area around the injection, not the entire tumor. And even if it annihilates the entire tumor, the therapy is powerless against any malignant cells that may have migrated elsewhere in the body. Even with the best results from these two tests, it will be at least three years before the FDA approves gene therapy for cancer outside of clinical trials.

Ray of Hope

But these two final-stage trials represent a ray of hope. And Introgen has also seen initial promising results in a Phase II, or midstage, lung-cancer trial that is a follow-on to earlier trials involving Ms. Aneff and others. In addition, doctors are testing p53 gene therapy for possible effect against prostate, breast and brain cancers.

"I don't think anybody harbors the illusion that you can take one gene off the shelf, inject it, and bingo, all tumors disappear," says James Zwiebel, an oncologist at the National Cancer Institute, which finances several gene-therapy trials. Still, he says that eventually, "it is very likely that p53 replacement therapy will become part of our standard treatment for some cancers."

Over the past several years, about 600 people have been infused with the p53 gene. The gene is known broadly as a "tumor suppressor," one of whose jobs is to sense when there is a problem with a cell and direct it to commit suicide. So it's a problem if the gene isn't doing its job.

The powerful role of p53 in human cancers was demonstrated by researchers at Johns Hopkins University 11 years ago. The gene -- which can be damaged by excessive sunlight, carcinogens such as cigarette smoke, or random duplicating errors during cell division -- is believed to be defective in 50% to 75% of human cancers, says Johns Hopkins professor Bert Vogelstein, whose lab did the pioneering work.

Useful Virus

To insert an intact copy of the gene into cells that lack one, scientists use a virus. Its harmful core is removed, and the p53 gene is inserted into the virus. The theory: The virus will do what viruses normally do -- infect cells. But instead of bearing a pathogen, they will carry in a beneficial gene.

In cancer, experimental gene therapy has caused some severe side effects such as high fevers, but it has proved less toxic than chemotherapy.

To date, 230 patients with head-and-neck cancer have been treated in three Phase II trials, says Antoine Yver, senior director of oncology gene research at Aventis, a drug company formed last year by the merger of Hoechst and Rhone Poulenc. Some tumors shrank dramatically. Others stopped growing -- not forever, perhaps, but long enough to buy the patient a few more months.

Of the patients, 6% saw their head or neck tumors shrink by half or more. While that was less than Aventis had hoped, by another measure the therapy was working better than expected: Overall, 26% of patients found their tumors either shrank or stopped growing. Looked at another way, given that some patients had more than one cancerous growth, 60% of the tumors injected either shrank or stopped growing for between two and 18 months.

This may not sound like much. But in the test group -- patients expected to live only about four months -- even a few extra months of life could be enough to win FDA approval, and possibly make this the first gene therapy on the market.

One doctor who took an early interest in the gene was Jack Roth, a lung-cancer surgeon who was frustrated by his enemy's power. "I was operating on a lot of patients, but it was clear it wasn't working," Dr. Roth says. "We needed to do something else."

Intrigued by the Johns Hopkins reports on p53, Dr. Roth began experiments in which the gene was shot into lung cells of special mice with human tumors. "The tumors didn't grow at all, or regressed," Dr. Roth says. After dozens of animal studies, he founded Introgen in 1992 to raise money for human trials. The Austin, Texas, company has filed to make an initial public offering; Dr. Roth owns 7% of it and stands to benefit if its IPO is a success.

In the first patient, a 60-year-old man with a lung tumor unresponsive to radiation, the cancer disappeared. "It was very exciting. It was the first clue something was going on," Dr. Roth says.

Then, in a reminder of the limitations of the therapy, the patient died four months later from another tumor, in his kidney.

Cold Virus

Although the patient's extra months represented an advance, the kind of virus used was difficult and costly to manufacture. Seeking another way to deliver the gene to cancer cells, Introgen turned to an adenovirus, a virus of the sort that causes colds. It was emptied of its normal contents, and p53 was inserted.

In association with Dr. Roth, Gary L. Clayman, a surgeon at M.D. Anderson Cancer Center in Houston, began using the adenovirus for experimental gene therapy on 33 people with head-and-neck cancer in 1995. Although steps had been taken to render the virus harmless, "we didn't really know" whether it could still cause harm, Dr. Clayman says. He wore a double set of gloves, washed carefully -- and worried about bringing home a virus to his newborn son.

The first few doses caused no ills, but no tumors shrank, either. Then researchers increased the dose a hundredfold, and began to see shrinkage. Introgen expanded the trials and began working with Aventis, which is financing the work in exchange for possible future marketing rights.

The patients in the expanded trials, all with advanced cancer unresponsive to other therapies, were expected to live only a few months. Gene therapy clearly had an effect, halting the growth of some tumors and shrinking some others. "The surprising thing for us investigators was that it worked at all," says John T. Hamm, an oncologist in Louisville, Ky. "Some people are disappointed that gene therapy hasn't revolutionized the world yet. It's a question of glass half empty or half full."

Leonard Taylor, a 50-year-old lawyer, was one of the lucky ones. He had a golf-ball-size tumor on his neck, which hurt his ability to chew and caused him to lose 40 pounds. It was too close to an artery for surgery. Chemotherapy shrank it at first but stopped working after six months.

Mr. Taylor then saw a newspaper ad for gene-therapy trials and signed up. He got his first shot in June 1998. Within three months, he was elated to find that the tumor had started to shrink. Now, nearly two years later, it appears to have disappeared except for a mass of scar tissue.

Doctors don't know if any live cancer cells are still present, so he goes back every month for another gene-therapy shot. "We're out there where no one has gone before," Mr. Taylor says. "We'll just take it one shot at a time and see how it goes."

The Safety Issue

Though the Jesse Gelsinger death raised alarms about safety, gene therapy for cancer is less toxic than chemotherapy. Two patients in Introgen's initial trial died for unknown reasons, leaving open the possibility that the therapy was responsible. But in a safety analysis prepared for federal authorities, Aventis found that, of 307 patients treated in Phase II trials for all types of cancer, there were no deaths, and only 3% had serious side effects, the most common being fever, infection or bleeding in the tumor. With chemotherapy, five times that many would have had serious side effects, Aventis's Dr. Yver says, and about 3% would have died. One reason for the relative safety of gene therapy for cancer may be that genes are injected into the tumor or right next to it, avoiding other parts of the body.

Shown this data, federal officials have largely let cancer trials continue, while halting several gene-therapy trials for other conditions. The government did stop an early-stage cancer trial at Schering-Plough, involving colorectal and liver tumors, pending a safety analysis. But Schering's final-stage ovarian-cancer trial will proceed.

Now comes the real test: large Phase III trials comparing gene therapy to standard treatments. In a trial Aventis and Introgen have just begun, about 240 people with head-and-neck cancer will be randomly assigned to get either the gene therapy or a mild chemotherapy drug. The test subjects will have cancer that has recurred, and they will be too frail for powerful chemotherapy or have cancer that hasn't responded to it. They'll have a median expected survival of four months; the goal is to see if the therapy can make them live about seven months.

"It works. Tumors shrink," Dr. Roth says. "The question is, does it work as well or better than existing treatments?"

There is ample reason for concern. In 1996, Novartis AG began the first Phase III trial of any kind of gene therapy, seeking to treat a deadly brain tumor called glioblastoma. The idea was to insert a gene that made the tumor vulnerable to a drug. Early trials had shown dramatic tumor shrinkage. But the big, final-stage one found that it didn't extend survival.

Aventis, hedging its bets, is also planning a separate trial to see whether gene therapy can make cancer cells more vulnerable to chemotherapy. A second 300-patient study will test p53 gene therapy in combination with a strong chemotherapy drug in head-and-neck cancers, compared with chemotherapy alone.

Therapeutic Combo

In lung cancer -- the most common cause of cancer-related death in the U.S. -- Introgen is just beginning a midstage test of the use of p53 and radiation together. The company says in its IPO filing that the results are "promising" and will be presented later this month before the American Society of Clinical Oncology.

In trial subject Charles Rogers, 67, the treatment appears to have killed a tumor about the size of a large lemon. "I can tell you I wouldn't be here today without the gene therapy," says Mr. Rogers, a retired insurance agent in Oklahoma. "It saved my life."

Dr. Yver is more cautious. "Normally, radiation alone does do something in these patients, so it's hard to tell which therapy is doing what," he says.

Meanwhile, Schering-Plough has licensed Johns Hopkins's initial patents on p53 therapy from Genzyme Corp., a Cambridge, Mass., company that owns the rights, and has tested p53 treatment in 200 patients in various cancers, with mixed results. In ovarian cancer, it was pleased with the outcome and has launched a final-stage study with patients who have already had surgery.

"There is no such thing as a magic bullet to cause all cancers to go away," says M.D. Anderson's Dr. Clayman. "All cancer treatment is incremental, and so is gene therapy."

HOUSTON -- Shares of Introgen Therapeutics Inc.  surged Tuesday after the company reported positive study results for its experimental gene-therapy treatment for cancer.

Introgen said 60% of patients' primary tumors regressed or disappeared after three months use of Advexin combined with radiation therapy.

The study at the University of Texas M.D. Anderson Cancer Center enrolled patients with nonsmall-cell lung cancer. The patients weren't eligible to receive surgery or combination therapy with radiation and chemotherapy.

"These results suggest that Advexin may enhance the effect of radiation therapy at the local tumor site without significantly increasing toxicity," Dr. Stephen Swisher, the principal investigator, said in a written statement. He added that further studies are needed.

It wasn't immediately known how many patients participated in the study.

Introgen has conducted more than 20 clinical trials of Advexin for the treatment of several types of cancer. The therapy looks to kill cancer cells and stop tumor growth without harming normal cells.

Introgen is conducting two controlled, randomized late-stage clinical trials with Advexin for the treatment of head and neck cancer, a mid-stage study in breast-cancer patients, as well as early-stage trials for people with prostate, ovarian, bladder, and brain cancers.

As of 4 p.m. trading Tuesday, shares of Introgen Therapeutics were up 80 cents, or 35.6%, to $3.05 on the Nasdaq Stock Market.