World's first gene therapy trial aimed at preventing cancer

But as yet no such "gene therapy" for cancer has ever been approved by the United States Food and Drug Administration (FDA).

Past attempts to inject therapeutic genes directly into solid tumors have shown promise, but researchers have stumbled over efforts to treat multiple tumors or cancer that has spread. That's because a patient's immune system reacts against the therapy, or the genes can't find their way to cancer cells.

Albert Deisseroth, M.D., one of the first gene therapy researchers at The University of Texas M. D. Anderson Cancer Center, has said of numerous early attempts, "Our challenge to design gene therapy has been many times more complicated than finding the proverbial needle in a haystack."

Still, new and ambitious approaches to gene therapy at M. D. Anderson are seen as encouraging to many of the researchers involved.

For example, a gene therapy strategy pioneered at M. D. Anderson is now on "fast track" approval at the FDA, the only gene therapy ever to be considered for approval for use in patients.

It has helped a number of lung cancer patients, including one who, at more than five years after treatment, is now the world's longest surviving gene therapy patient.

And, at the opposite end of the spectrum, M. D. Anderson is conducting the world's first gene therapy trial aimed at preventing cancer. Patients at risk of developing oral cancer gargle a concoction twice a week that coats their throats with protective genes.

Researchers are testing a variety of novel approaches - wrapping genes in bubbles of fat, using a virus that ignores healthy cells, employing powerful stem cells - to deliver genes to both tumors and hidden cancer cells.

To date, at M. D. Anderson, gene therapy experiments are ongoing, or starting within several months, in metastatic lung cancer, head and neck cancer, and brain cancer. These studies are part of an ever-expanding "platform" of research that is devising next generation gene therapy designed to both effectively tackle other cancers and to be the safest treatment possible.

Researchers predict these therapies likely will be used in combination with other treatments until the time comes when genetic profiles can be developed of each individual person's unique cancer. Then, therapies tailored exclusively to the patient can be developed, and gene therapy may ascend, says Jack Roth, M.D., an M. D. Anderson researcher who is nationally known for his pioneering gene therapy work.

"In time, targeted gene therapy may help improve the outlook for many types of cancer," says Roth, director of the W. M. Keck Center for Cancer Gene Therapy at M. D. Anderson. "While we have a long way to go, I am increasingly optimistic about new gene therapy approaches to earlier treatment and, ultimately, to a strategy that may help prevent cancer development."

The beginnings

The evolution of cancer gene therapy began at M. D. Anderson more than a decade ago when two researchers undertook a set of landmark gene therapy studies.

Deisseroth, then chairman of the Department of Hematology (and now president of the Sidney Kimmel Cancer Center in San Diego), was the first to try an experimental gene "augmentation" program in patients. His idea was to modify bone marrow cells, in patients who had either breast or ovarian cancer, with a gene designed to protect patients against resistance to chemotherapy drugs. In that way, the patients could receive larger, more beneficial doses of chemotherapy drugs. But the tests, conducted in 20 patients, were not successful because of the low amount of the vector taken up by the bone marrow cells.

Roth, now chairman of the Department of Thoracic and Cardiovascular Surgery, had more success. He found that an abnormal or missing p53 gene in lung tumors could be successfully replaced in experimental animals. The p53 gene, which normally acts as a brake against uncontrolled cell growth, is missing or mutated in about half of human cancers, and dysfunctional in most of the rest.

Based on the animal experiments, the first lung cancer patient underwent gene therapy in early 1995, and in mid-1996, Roth and his group published a study describing the first reported successful replacement of a defective p53 tumor suppressor gene. M. D. Anderson licensed the finding to the biotech company, Introgen, which Roth helped create and for which he is now a paid consultant. "It all started here at M. D. Anderson with the concept, vector development, preclinical trials and the first phase of testing," says Roth. "This agent has clinical benefit, and because of its novelty and lack of interest by major pharmaceutical companies, the only way to make it available to patients was to start a biotech company. But it has been a long road."

Introgen conducted phase II studies on the therapy, which it calls Advexin, and found that lung tumors shrank in over half of the patients who used it when combined with radiation therapy. Moreover, there have been unexpected long-term survivors, and these findings have sent the company to the FDA for fast track approval, which is currently being considered. More than 20 completed or ongoing trials are testing Advexin in such solid tumors as lung, head and neck, breast and ovarian. Some of these trials are now ongoing at M. D. Anderson, as well as at other cancer centers around the world.

But the drug has limitations. It uses an adenovirus, the microbe that causes the common cold, as a "vector" - a sort of taxicab - that carries genetic material directly into cancer cells. The virus is disabled, but is considered a short-term therapy that must be constantly repeated.

Adenovirus-based therapies, which are the most commonly studied cancer gene therapy vehicles, work well when they are injected directly into a tumor. But because they are by their nature an infectious agent, these vectors can produce systemic immune reactions in patients when delivered throughout the body by intravenous injection.

It was a fatal immune reaction to an experimental adenovirus-based therapy that abruptly halted gene therapy research nationwide in 1999, when 18-year-old patient Jesse Gelsinger died while participating in a University of Pennsylvania clinical trial. The study wasn't about cancer, but was designed to treat a rare metabolic disorder. Another experiment in France using a virus vector succeeded beautifully in curing young patients of a critical immune deficiency disease, but also caused leukemia in two patients. The gene that was delivered settled itself next to an oncogene, and turned it on.

After each incident, the federal government shut down related gene therapy clinical trials for a period of time and has increased oversight of all clinical trials.
While there have been no similar serious reactions to adenovirus-based cancer gene therapies, the major hurdle any such therapy faces is treating cancer that has spread. "The obstacle in dealing with malignancy is facing the dissemination of disease - its spread," says Gary Clayman, M.D., another gene therapy researcher at M. D. Anderson. "Therefore, a clear barrier to gene therapy is addressing that spread in an effective way."

Fat bubbles

Bubbles of fat may offer an answer. The newest strategy to emerge out of Roth's lab is a blob of lipid, a type of fat that holds therapeutic genes. Developed by Nancy Templeton, Ph.D., of Baylor College of Medicine, the special "liposome" is of a size that is easily absorbed into cells. "Dr. Templeton hit upon a liposome size that had a very efficient transfer into cells," says Charles Lu, M.D., an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology and co-investigator.

The liposomes carry a new payload as well. They encase, like shrink wrap, a normal p53 gene as well as a second gene, FUS1, which is frequently altered or missing early in the development of many solid tumors.

So far, six patients with metastatic lung cancer have been tested with the therapy in a phase I trial headed by Lu. In all, 30 patients are expected to be enrolled. The trial is a "dose escalation" study, which looks for side effects as doses of the drug are increased. "So far, there have been no significant safety issues," says Lu.

The study is the first to test liposome therapy in treating human cancer, according to Lu. "No one before has tried intravenous injections using liposomes to replace genes that are lost or defective. This non-viral aspect is very different in gene therapy. It may offer major benefits because liposomes are non-infectious. They are inert; there are no infection risks to use bubbles of fat.

"If successful - and that is a very big if - liposomes may prove to be a way to deliver gene therapy systemically, potentially treating metastatic disease in multiple cancer sites," says Lu.

What isn't known yet, however, is how often normal cells will absorb the drug and what effect that will cause. Preclinical study seems to show that tumor cells preferentially take up the bubbles - and researchers are pleased with that finding, although they don't know why it happens - but healthy cells can also sop up the new genes. "It may not have too much of an effect on normal cells because they already have these beneficial genes, but we just don't know yet," says Lu.

While Lu describes himself as "very cautious; it's just a proof of a concept right now," he also says he is "excited, because it took so much to get to where we are now."

Not only did the science need to advance, but there was "tremendous regulation" through reviews at the federal level and at M. D. Anderson.

Roth is already busy perfecting the liposome therapy by testing the delivery of other genes as well as modifying the liposome coating. "My goal is to move the use of this therapy away from patients who have no other options because these cancers are extremely difficult to treat and the response rates are always low," he says. "The best uses of gene therapy will probably be in earlier stages of cancer or as part of primary treatment when cancer is first diagnosed."

A virus for the brain

The old saw goes that if curing cancer in mice was the same as curing it in humans, we would have won the war on cancer a long time ago.

While the point is taken, researchers at M. D. Anderson who last year cured brain cancer in mice were amazed because no one had ever before tested a drug that had any effect on malignant glioma, the most deadly of brain cancers.

Testing a gene therapy in mice, likened to a "viral smart bomb," the M. D. Anderson scientists found only empty cavities and scar tissue where human glioma tumors had once been. The therapy, known as Delta-24-RGD, had moved like waves throughout the brains of the mice, killing the cancer while leaving normal tissue intact.

While the treatment employs an adenovirus, it does not seem to produce toxic effects in the brain, say researchers. In fact, the mice tested were considered clinically cured of their brain tumors with little known side effects.

These animal tests, reported last year, were considered so promising that the National Cancer Institute moved immediately to produce, in its own labs, a clinical-grade version of the therapy, and scientists with the FDA began collaborating.

"We've never seen this kind of response before with any other treatment tested in either animals or humans," says the lead author of that study, Juan Fueyo, M.D., an assistant professor in the Department of Neuro-Oncology.

"Biologic viral therapy like this may be just what we need to treat a complex disease like cancer," says co-author Frederick Lang, M.D., an associate professor in the Department of Neurosurgery when the study was published. "Cancer can be devious in that it does everything possible to evade destruction. But viruses are equally tricky in their quest to invade cells and propagate."