Science / Medicine : Human Gene Joins War on Disease : Cancer: Researchers get go-ahead for experiments designed to stimulate production of enzymes or hormones to battle disorder. Procedure seen offering hope to those with incurable ailments.
The idea of using human genes to treat diseases, virtually science fiction just two decades ago, may soon become medicine’s newest hope for battling cancer and other life-threatening, even incurable disorders.
Researchers at the National Institutes of Health are about to embark on a series of dramatic new experiments involving the use of genes that could usher in a new era in medicine and transform the outlook for many such critical conditions.
The go-ahead came last week, when Dr. Steven A. Rosenberg, a leading cancer researcher and chief of surgery at the National Cancer Institute, and his NIH colleagues received a long-awaited and crucial go-ahead to conduct two experiments that for the first time will attempt to insert “foreign” genes into humans in order to treat disease.
The projects themselves are delicate--and complex. Researchers plan to take normal genes that have been developed in the laboratory and insert them into the cells of patients in hopes of stimulating the production of disease-fighting enzymes or hormones. The NCI’s Rosenberg will perform his experiments on patients suffering from melanoma, a potentially lethal skin cancer.
An associate, Dr. W. French Anderson of the National Heart, Lung and Blood Institute, will perform his on children who have adenosine deaminase deficiency, a rare inherited immune system disorder that afflicts only about 30 youngsters worldwide at any one time.
“We’re dealing with a problem of extraordinary magnitude,” Rosenberg says. “One out of every five or six Americans will die of cancer. No family will be spared. It’s an astonishing thing, when you think about it. More Americans die in a single year from cancer than died in World War II and Vietnam combined.”
Dr. Theodore Friedman, professor of medicine at UC San Diego and one of the early proponents of human gene therapy, agrees that venture could prove to be a milestone. “Throughout the history of medicine, we have treated diseases aimed at the consequences of the defect, not at the defect itself--such as treating hemophilia with clotting factor, or diabetes with insulin,” Friedman says. Now, however, with the application of sophisticated genetic engineering techniques, “we’ve finally come to recognize in principle that the treatment of disease at the level of the genes makes sense,” he says.
Scientists warn that the venture still is a gamble, and may not yield the results they seek. But Rosenberg and his colleagues are excited. If the experiment works, he says, melanoma could be only one of numerous cancers that potentially could benefit from human gene therapy.
Indeed, Rosenberg has spent virtually his entire career trying to develop therapies for the estimated 50% of cancers that cannot be cured by the usual means--surgery, radiation or chemotherapy. This translates into an estimated 500,000 persons annually.
Dr. Sam Broder, director of the National Cancer Institute, says the acceptance of the new experiments represents “a major change, a major shift in the history of biomedical science” that could have an “important impact on cancer, AIDS, heart disease--in virtually every medical discipline.”
The very notion is mind-boggling. There are about 50 trillion cells that make up the human body. Each contains information that directs its function. This information is stored in the genes, which are made up of DNA--the genetic blueprint of life. When a gene is destroyed or broken, the cell’s function is disrupted or eliminated and disease occurs.
There are two basic approaches to gene therapy: Scientists can introduce a normal gene in an attempt to correct a defective gene or replace a missing gene. Or the normal genes can be used to assign a cell a new function or enhance its current function.
The proposed treatment for the immune deficiency involves replacing a gene that stimulates production of adenosine deaminase, an enzyme that is crucial to the proper functioning of the immune system.
Anderson and his colleagues plan to grow the patient’s own white cells in a laboratory, add the critical gene, then return the cells to the patient’s body with the hope that the new cells will stimulate production of the enzyme, thus restoring the immune system.
“This is the fascination and promise of gene therapy,” Rosenberg says. “It attempts to prevent or alter disease by altering the internal makings of the human, rather than by applying an external force--like a scalpel.”
Friedman and many other scientists believe that all human diseases--even such classic genetic disorders as Huntington’s disease, cystic fibrosis and Tay-Sachs disease--are probably a consequence of “the interaction of genes with the environment.”
Pioneers in the field of human gene therapy say that the action last week of NIH’s Recombinant DNA Advisory Committee in approving the projects signals the validation of theories that began about 20 years ago with the rather unconventional proposition that basic genetic defects could be corrected or modified directly within human cells.
In those days, such ideas were only supposition. Scientists were not equipped with the tools or knowledge to isolate and reproduce genes, or insert them into human cells. But the last two decades have produced an explosion of advances in genetic engineering technology that has made such procedures in the laboratory well-established.
“Back then, we were not considered to be talking serious science,” says San Diego’s Friedman. “But if we’ve learned anything in science, it’s the speed with which today’s impossible quickly becomes tomorrow’s usual.”
Several treatments for the immune disorder already exist. These include bone marrow transplantation, which is not often successful, and a new drug called PEG-ADA, approved by the FDA last March, which replaces the enzyme and has been effective in many cases. Still, the incidence of the disease is rare.
Melanoma, on the other hand, strikes an estimated 28,000 people annually, and kills about 6,300. Moreover, it has been decidedly on the rise in recent years, increasing at the rate of about 4% a year, according to the American Cancer Society. If detected very early, melanoma can be cured by surgery. Advanced melanoma, however, does not respond to any known treatment. Most patients in this stage die within about four months.
If the experiment works, melanoma could be only one of numerous cancers that potentially could benefit from human gene therapy. This is why Rosenberg is so excited about it.
Rosenberg’s approach has been to find ways that use the body’s immune system--its own natural defenses against disease.
“The body is normally doing battle against cancer, but the battle is favoring the cancer,” Rosenberg says. “The body’s defenses are not strong enough. All of the work I’ve been doing has been to develop ways to enhance the body’s own defenses.”
In recent years, Rosenberg has conducted pioneering studies that have shown that certain types of white blood cells in the immune system can be dispatched in the fight against cancer.
Several years ago, in fact, Rosenberg achieved some success with several melanoma patients using lymphokine-activated killer (LAK), a type of immune system cell that he and his colleagues discovered, in conjunction with interleukin-2 (IL-2), a substance that stimulates cell-replication. IL-2, a natural substance secreted by the body in small amounts, can now be mass-produced through genetic engineering.
In the new melanoma study, Rosenberg and his colleagues will try to create a kind of super-cell, which he calls a “designer lymphocyte.” They will add a key gene to so-called tumor infiltrating lymphocytes (TILs), cancer-fighting cells found to be even more potent than LAK cells. The researchers believe TIL cells are different from other immune system cells in that they hone in on--and accumulate--only in tumors.
The new gene will be coded to stimulate the production of a powerful hormone, tumor necrosis factor (TNF), which Rosenberg hopes will boost the ability of these cells to attack and destroy tumors. The TILs will be taken from the patient’s tumor, modified with the new gene, and then put back into the patient.
“TNF is a molecule that has shown dramatic anti-tumor effects in mice,” Rosenberg says. “If you give it to mice, you can make their cancers go away.” But when TNF has been injected into humans, it has had no effect on their cancer. Rosenberg believes this is because mice can tolerate 40 times the level of TNF as humans can, and “it takes that 40 times more to cause an anti-tumor effect.”
However, since TILs zero in only on the tumors, scientists hope they can deliver TIL cells directly to the tumor and use them as “factories” to produce the TNF right where it is needed and in doses high enough to kill the cancer, but not the patient. “The whole rationale is to have the TILs make this extra amount of TNF only at the tumor site, not throughout the body,” Rosenberg says.
If this works, he says, the approach will result in a significant gain over current chemotherapy, which kills healthy cells in addition to diseased ones.
“The major advantage of the immune approach is its exquisite sensitivity and specificity in recognizing the difference between a cancer and a normal cell,” Rosenberg says.
Those receiving experimental treatment will be persons who have advanced melanoma, whose other options have been exhausted. “It’s a desperate patient population, in desperate need of help,” Rosenberg says.
Under the procedures that Rosenberg is planning, surgeons will remove a piece of tumor under a local anesthetic, and then send the patient home for about a month. For the next 30 or 40 days, the NCI scientists will grow billions of TIL in the laboratory, using IL-2 to promote replication.
The researchers will then use a retrovirus (a virus that inserts its own genes into the DNA of a cell), which they have rendered harmless, to carry new genes into the cells. They will actually insert two genes--one containing the information for tumor necrosis factor, and a second to make the cells resistant to neomycin, a powerful antibiotic. That antibiotic will later be used in the culture to kill excess cells that do not contain the genes--creating a pure pool of gene-modified TIL.
When the patient returns the next month, a milky white solution containing billions of gene-modified TIL cells will be infused in his body, along with a separate dose of IL-2. Additional infusions of IL-2 will come every eight hours for the next three or four days, to keep the cells alive in his body. He will return for three more infusions.
Rosenberg believes the procedure has few risks, since the researchers will be giving the patient back his own cells. Also, the gene produces a substance that is normally found in the body anyway, so rejection is not a problem, Rosenberg says.
Rosenberg says that since TIL can be found in virtually all kinds of malignant tumors, such an approach--if it works--holds the promise for widespread application in treating other malignancies.
Rosenberg concedes there are still numerous problems to overcome, including developing more effective ways to grow TIL. “It’s very important not to raise unrealistic expectations,” he says. Nevertheless, he finds it hard to contain his growing enthusiasm over its potential.
“There are problems that need to be surmounted, but I think it’s eventually going to work,” he says. “Hopefully, it will work soon.”
Designer Cell to Fight Cancer
1. Tumor is removed surgically.
2. Tumor cells are incubated with interleukin-2 (IL-2), which stimulates the existing tumor-infiltrating lymphocytes (TILs)--critical immune system white cells--into replicating themselves.
3. TILs from the tumor begin to proliferate--while cancer cells die--leaving only TILs.
4. A retro-virus containing genes that have been coded to produce tumor-necrosis factor (TNF), a powerful cancer-fighting hormone, is introduced into TILs.
5. Result: TILs now contain new cancer-fighting genes.
6. Finally, “gene-modified” TILS and IL-2 are infused into the patient in hopes that the new “designer” cells will stimulate the production of large amounts of TNF in the tumors.
Source: National Cancer Institute
