Genetic Engineering Yields Disease - Fighting Hormones

by Food and Drug Administration (FDA)

Many of the products described in this article have not yet gone through FDA's approval process. The therapeutic uses described should therefore be understood as investigational, not proven.

While waiting for a kidney transplant, June was treated by a blood-washing machine three times a week. Nevertheless, she became weak, was sometimes dizzy, had rapid heartbeats, and tired easily. Her doctors recognized the problem immediately. Like many patients on chronic dialysis for kidney failure, June had developed anemia; she wasn't making enough red cells to carry sufficient oxygen around her body.

Previously, the treatment for anemia was blood transfusions. But in this composite case, based on several studies in the medical literature, the doctors would be able to start June on a substance called erythropoietin (EPO), a hormone that stimulates the body to make red blood cells.

The function of EPO has been known for more than 30 years. It is one of a group of substances known collectively as hematopoietic growth stimulating factors, which are a type of cytokine (see accompanying article). However, EPO was unavailable for patients because it was difficult to purify large enough amounts.

This situation began to change in 1977 when scientists were able to identify the gene that controls the hormone. It was then a relatively simple matter for molecular biologists to isolate the gene and insert it into animal cells that could then synthesize unlimited quantities of the hormone.

EPO is now available in amounts sufficient to treat patients like June — indeed the agent was licensed by the Food and Drug Administration last summer for just this very purpose. In addition, thanks to similar genetic engineering manipulations, an increasing number of factors that stimulate the production of other cells in the blood besides the red cells also are being brought into use. These include the all-important cells that regulate the immune system enabling the body to fight off infectious invaders.

A wide variety of clinical studies are under way to explore the potential of these agents to improve the management of patients receiving anti-cancer drugs, many of which depress the cells of the immune system. They may also be able to help patients with anemia and those with immune system disorders, including AIDS.

New Era

In short, some new and remarkably powerful therapeutic tools are about to become available, putting physicians and their patients at the door of a new era in medicine — comparable, say some authorities, to the advent of antibiotics half a century ago.

But before these agents can be used in everyday practice, the sponsor — that is, the manufacturer who wishes to put these products on the market — must adequately test them for safety and efficacy. Possible risks with the use of the agents also have to be evaluated. Responsibility for ensuring that this is done adequately falls on FDA (see accompanying article).

Hematopoietic growth factors orchestrate the blood-forming machinery of the body. All blood cells develop from a parent cell in the bone marrow. In response to the demands of the moment (such as excessive blood loss, infections, or simply the routine replacement of worn-out cells), the body makes red cells that carry oxygen, platelets that control clotting, and white cells that are essential to the proper functioning of the immune system.

This process is controlled by growth factors, which play a role in the differentiation and production of certain blood cells, and in the activation of immune system cells in response to infectious agents. Because these hormones stimulate the production of colonies of these cells, they are called colony stimulating factors (CSF).

A number of potential human hematopoietic growth factors have been identified. (See accompanying chart.) The genes that provide the instructions to make the factors have been isolated and inserted into cells that can produce the hormone in quantity.

Three of the principal types of white cells are granulocytes, monocytes and lymphocytes. Growth factors get their names from the type of blood cell they stimulate: granulocyte stimulating factor (G-CSF) stimulates formation of granulocytes; M-CSF stimulates monocyte formation; and GM-CSF stimulates both granulocytes and macrophages (another cell of the immune system).

Leukemia Patients

Many leukemia patients have low levels of granulocytes. Jordan Gutterman, M.D., of M.D. Anderson Cancer Center in Houston, has found that treatment with GM-CSF or G-CSF can increase the number of granulocytes.

Gutterman is interested in seeing whether it is possible to overcome the reduction in white blood cells that follows cancer chemotherapy and which makes cancer patients readily susceptible to infections. For, although chemotherapy destroys cancer cells, it also kills other rapidly dividing cells, including the disease-fighting white blood cells of the immune system. Indeed, reducing the incidence of infection caused by low levels of white blood cells following chemotherapy is the primary goal in using these colony stimulating factors in cancer patients.

Gutterman concludes from preliminary clinical studies that agents such as GM-CSF can shorten the time when these guardian cells of the immune system are at particularly low levels. The result is fewer infections and less need for anti-biotics.

For example, in one of Gutterman's studies, 25 advanced bladder cancer patients could not be given chemotherapy because their immune system cells were dangerously low. With GM-CSF these cells were restored sufficiently to allow these patients to receive treatment. Indeed, 45 percent of this group of patients improved after chemotherapy.

At a workshop recently held by FDA (see accompanying article), Janice Gabrilove, M.D., of the Memorial Sloan Kettering Cancer Center in New York discussed a study in which the number of patients able to receive the planned regimen of chemotherapy tripled — from about one-third to 100 percent — with the use of GM-CSF. Since inability to complete effective courses of chemotherapy is associated with treatment failure, Gabrilove's results suggest that the use of GM-CSF could result in higher success rates.

GM-CSF may also enable patients to tolerate higher doses of chemotherapy. However, it still has to be proven that doses of anti-cancer drugs above those presently in use have beneficial effects.

Questions Remain

As promising as current research seems, questions still remain. Gutterman noted the possibility that repeated doses of GM-CSF or G-CSF might exhaust the bone marrow where the cells originate, but said there is no evidence yet that this occurs. Indeed, so far all the evidence is the other way. Another potential problem is the possibility of stimulating tumor cell growth itself. Again, the evidence from laboratory studies is that this is not a major concern. "But both these issues need careful discussion," Gutterman said.

Potential toxicity is always a concern with any new agent, and, although adequate responses to the hematologic growth factors have been obtained without toxicity in most instances, treatment with high doses of GM-CSF in very high doses has given rise to leaking blood vessels, inflammation of the sac surrounding the heart, and other inflammatory complications, Gutterman noted. However, he added, adequate clinical responses have been achieved with nontoxic doses.

The outlook for patients who have unsuccessfully undergone bone marrow grafts for leukemia or aplastic anemia is very poor, according to Frederick Appelbaum, M.D., of the Hutchinson Cancer Research Center in Seattle. Fewer than 10 percent of such patients survive for 12 months.

"We tried GM-CSF on one patient who, 40 days post-transplant, had a granulocyte count of 50," Appelbaum said. With granulocytes at this level there is a high risk of infection. "Five days after giving GM-CSF his granulocytes were over 1,000. In two weeks 5,000. The patient continues to do well, more than a year and a half later," he added. (Normal granulocyte counts range between 3,000 and 7,000.)

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