World's first gene therapy trial aimed at preventing cancer

The concept seems straightforward. If, at its heart, cancer is a disease of genes, then giving patients new genes should disarm cancer. Such treatment would replace missing or faulty genes that keep cell growth in check, or would flush the body with "super genes" that could attack and destroy 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."

Now, Delta-24-RGD is expected to start the first phase of human testing in late summer 2004, with a two-staged clinical trial of 15 patients each. One stage will offer the treatment by injection to patients with recurrent gliomas who cannot be treated with surgery. Progress will be monitored with serial diagnostic scans. In the second stage, patients with a glioma will have the therapy, followed by surgery two weeks later. The excised tumor will be examined to see if it has been damaged.

This trial is just part of an ongoing larger "platform" of research that is continually refining Delta-24-RGD therapy, says Charles Conrad, M.D., an associate professor in the Department of Neuro-Oncology who works with Fueyo, Lang and others on the "Delta team."

They have already created a second and now a third generation of the therapy, each of which is proving more adept in infecting cancer cells and disarming them. One idea is to insert genes into the viral smart bomb that will switch on chemotherapy drugs. This way, a patient could receive an inert form of a chemotherapy drug that would be non-toxic to normal cells, but would be activated by the Delta virus when it spreads in cancer cells. "We would deliver the gene that activates the chemotherapy drug only to tumor cells," says Conrad.

The team, which includes other international and national investigators, also is exploring adapting Delta-24-RGD to other cancer types, such as colon cancer. Questions remain, however, as to whether the therapy will evoke a systemic immune response and just how the virus will be able to spread given physical barriers - such as bones or cavities - that are just a natural part of the body's interior. Many solid tumors also contain areas of dead tissue, which could stop the virus's ability to replicate. Finally, researchers are concerned about the issue that has dogged all adenovirus vectors - that, below the neck as it were, a patient could mount an immune response that would blunt the effectiveness of the therapeutic virus.

"We will have our proof of principle in treating gliomas," says Conrad. "If it is safe, and shows some benefit, we will want to try it in other cancers."

Naked genes

Gene therapy's limitations may prove to be a boon to one area of cancer treatment. Knowing that, at least to date, the strategy works best when injected directly into tumors, M. D. Anderson researcher Gary Clayman is using "topical" gene therapy to treat patients at risk of developing oral cancer.

The first of a planned 44 patients has been enrolled in the phase I/II clinical trial, funded by Introgen, in which participants will gargle twice a day with a solution intended to replace the p53 gene that is likely missing from cells that are within several millimeters of the surface of their mouth and throat.

"This is more befitting of what this technology may be able to offer," says Clayman, M.D., a professor in the Department of Head and Neck Surgery. "The cells we need to treat are near the surface. We don't need to go deep. It's not a systemic disease."

There has been no way to prevent development of these head and neck cancers, and once they arise, they are diffuse and difficult to treat, says Clayman. But if a treatment can reach the thin layer of cells from which the cancer arises, it may be possible to reverse or even kill the cancer, he adds.

The trial, conducted only at M. D. Anderson, is the first to test a preventive cancer strategy using a novel gene therapy, says Clayman. He believes that while other forms of gene therapy have shown suggestions of clinical activity, "translation to clinical utility may not be there. We need to focus on the limited ways in which gene therapy may truly help patients."

Gene therapy for metastasis

Others at M. D. Anderson heartily agree that most of the current gene therapy strategies do not effectively address the thorniest problem in cancer care - treating cancer that has spread - and that is why they are breaking new research ground.

One team has already harnessed the power of stem cells to act as seek-and-destroy missiles that can find cancer wherever it hides out - at least, so far, in animals.

This novel treatment, which was presented last year at a scientific meeting, takes advantage of the fact that tumors attract a certain kind of stem cell, mesenchymal progenitor cells (MSC), which acts as the body's natural tissue regenerators. These unspecialized cells migrate to an injury by responding to signals from the area, and there they develop the kind of connective tissue that is needed to repair the wound, and can become any kind of tissue required.

But they also respond to tumors - often described as "never healing wounds" - which "call" the stem cells to help build up normal tissue that is needed to support the cancer.

So a research team led by Michael Andreeff, M.D., Ph.D., professor in the Departments of Blood and Marrow Transplantation and Leukemia, is turning the tables on the cancer.

In experiments in mice, they have removed a small amount of MSC from bone marrow, expanded the quantity in the laboratory, and genetically altered the stem cells to carry a therapeutic gene. When given back to the mice through an intravenous injection, the millions of engineered stem cells home in on cancer cells that are signaling them, engraft and activate their genetic payload, which then disables the cancer.

So far, the therapy has been successfully tested in mice that have a variety of human solid cancers, such as ovarian, brain, breast and melanoma, and even blood-based leukemia.

"This drug delivery system is attracted to cancer cells no matter what form they are in or where they are," says Andreeff. He is planning to apply for federal permission to test the concept in patients with melanoma.

"We will need to optimize the genes that are delivered, and are building a program around that, but the most important discovery here is that these cells are capable of migrating from the bone marrow or blood circulation into tumors," says Andreeff.

"It is exciting because it is an entirely new approach that looks like it can be developed into a potent therapy," he says. "It's not just a twist of an old idea."