Genetic Engineering Yields Disease - Fighting Hormones : Part 2

by Food and Drug Administration (FDA)

(Page 2 of 2)

Survival Increases

As a result of this experience, the Seattle group started a study of the use of GM-CSF in patients experiencing marrow graft failure. Of 15 patients given grafts from unrelated donors, nine had an increase in granulocytes. Eight of the patients have survived more than three months. Without GM-CSF, Appelbaum said, "we would expect only three or four of these patients to be living." In another study of a group of 23 patients given grafts from close relatives and then treated with GM-CSF, 16 have survived.

Overall, there may be a dramatic decrease in deaths among these patients. A study by William Peters, M.D., of Duke University showed that before the advent of GM-CSF there was a 21 percent mortality rate among a group of transplant patients. After GM-CSF was introduced this was cut to 12 percent.

Use of these factors may also reduce the cost of marrow transplantation. Citing data from the Seattle group, James Armitage, M.D., of the University of Nebraska, noted that the median hospital stay of marrow transplant patients not receiving GM-CSF was 41 days. But in patients treated with GM-CSF it was only 26 days — a one-third reduction.

"If you figure the cost of hospital stay at $3,000 per day then you are cutting the cost of transplantation by between $30,000 and $40,000 per patient," he said.

Patients whose bone marrow fails early in life or from some unknown cause are especially difficult to treat. But even in these cases, there is encouraging, if preliminary, success. Many are infants and children, and all inevitably face long-term treatment by conventional methods. At Sloan Kettering, Gabrilove and her associates have so far treated five such children with G-CSF. The levels of their immune cells went up, accompanied by a fall in the number of infections they had compared with a similar period before treatment.

Iffy AIDS Treatment

In patients with AIDS (acquired immune deficiency syndrome), the use of hematopoietic growth factors is still in its early experimental stages. GM-CSF, by itself, may actually stimulate the multiplication of the AIDS virus. Scientists theorize this may happen because GM-CSF stimulates the immune cells that the virus infects.

Robert Yarchoan, M.D., of the National Cancer Institute, noted that he and his associates have found increased levels of one of the proteins present in the shell of the AIDS virus in cells stimulated by GM-CSF. "We think this is a concern, although not an overriding one," he says. "But, certainly it will have to be carefully evaluated."

On the positive side, there is good laboratory evidence that GM-CSF in association with AZT may slow down the multiplication of the AIDS virus more efficiently than AZT by itself, Yarchoan says, citing a report in the March 1989 Journal of Experimental Medicine.

When used with AZT, GM-CSF might both increase the number of white blood cells and stimulate the activity of the drug against virus infecting the cells. The National Cancer Institute is investigating the combined use of AZT and GM-CSF in patients, but there are no findings yet.

Waiting in the Wings

Though these are currently more widely studied applications of the hematopoietic growth factors, waiting in the wings are potential treatments for a variety of other conditions. For example, burn patients frequently have low white blood cell levels and might respond to treatment with agents that stimulate white cell production.

There are already experimental cancer treatments that involve marking tumor cells with antibodies so they can be detected and destroyed more effectively by immune system cells. This process could be made more efficient by increasing the level and activity of these cells using colony stimulating factors.

Until now, strategies for treating disease have been based on attacking the invaders, inactivating them or reducing their numbers — whether they be viruses, bacteria, or other disease-causing agents. But the advent of colony stimulating factors puts into the hands of tomorrow's physicians the means of not just helping immunity but of creating a more efficient immune system.

Cytokine Workshop

With the development of technologies capable of producing large amounts of the regulatory growth factors that affect differentiation and proliferation of cells, including those of the immune system, researchers have started to study their uses in a variety of clinical conditions. As these studies progress to human trials, the sponsors submit investigational new drug applications to the Food and Drug Administration, which evaluates them for licensure and clinical use.

As part of the attempt to define and resolve important questions, clinical and basic scientists and FDA exchange information on what is currently known about these factors. To help expedite this process, FDA's division of cytokine biology recently held a workshop to explore the present state of the science and the emerging clinical uses of these growth factors.

"From an evaluation of the scientific issues come the right regulatory decisions," said Gerald Quinnan, M.D., deputy director of FDA's Center for Biologics Evaluation and Research, opening the workshop. The accompanying article about these growth factors contains discussion of studies presented at the workshop.

FDA established the cytokine division in October 1988 in response to the rapidly growing amount of research in this new field. The definition of the word "cytokine" in the division's title is itself in flux. Originally the use of the word was limited to those protein molecules that encourage growth of the cells of the immune system, to distinguish them from factors that stimulate growth of cells outside the immune system. However, these boundaries are becoming blurred, especially since it is now known that the two classes of molecules have many similarities. Furthermore, cytokines also have effects on cells other than those of the immune system.

The cytokine division's director is Kathryn Zoon, Ph.D., and the division consists of four laboratories: cytokine research, cellular immunology, cell biology, and molecular immunology. Since it was formed, the division's personnel has doubled. It is currently handling well over 400 investigational new drug applications and 10 major product license applications and amendments.

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