Body’s Cells Mobilized in Novel Fight of Infection

Not since a wayward mold blew into a laboratory window 60 years ago to contaminate a culture dish, accidentally triggering the age of antibiotics, have scientists voiced such excitement over a new class of pharmaceuticals.

Colony stimulating factors--words sometimes spoken in an awe of their dazzling potential--have captured the imagination of medical science as little has since the advent of penicillin. Ultimately, they could become potent biologic weapons in the fight against cancer, infections, radiation sickness, massive burns and possibly even AIDS.

Like antibiotics, colony stimulating factors (CSFs) aid the body in its fight against infection. But CSFs, unlike antibiotics, are derived from the human body itself.

Because the body is an apothecary of disease-fighting capability, potentially more efficient than synthetic antibiotics, scientists who have cracked the DNA codes of the factors believe they are now on the threshold of harnessing nature’s own pharmacy.

Avoid Extreme Terms

They have found a way to manipulate production of the immune system’s key white cells, those that constitute a surveillance and attack network against infection and disease.

But scientists bite their tongues to avoid terms such as “wonder” or “miracle” when referring to the yet-to-be-approved drugs. Most, like Dr. David Golde, chief of hematology and oncology at the UCLA School of Medicine, spell out their accolades carefully, looking toward a day when CSFs will become therapies of choice.

“I am very optimistic,” declared Golde in his lab, where some of the country’s most significant developments in gene technology have occurred in recent years. “I think this is one of the biggest advancements since antibiotics.”

“They’re so new,” said cell biologist Peter Ralph in charge of the CSF project at Cetus, an Emeryville, Calif., biotechnology company, “that it might be surprising to most classical drug development people that they work at all.”

CSFs are minute hormones--protein molecules--produced naturally by the body in quantities so small their presence sometimes escape detection. But their importance--regulating the type and quantity of blood cells in the circulatory system at all times--far outweighs the paucity of their number.

‘Very, Very Potent’

The hormones are responsible for a daily production of billions of blood cells and derive their name from their function--stimulating production of certain “colonies” or groups of cells.

“They’re dilute but very, very potent,” said molecular biologist Philip Whitcome of the Amgen biotechnology firm in Thousand Oaks, describing the concentration of CSFs in human blood.

“If you drained all of the blood out of your body, you wouldn’t have enough of these factors to put on the head of a pin,” he said.

Increasing the population of circulating white cells can augment the body’s capability to battle infection, the prime motivation for CSF therapies. White cells are also important because of their uncanny locomotion, allowing them to move against the bloodstream or migrate through the walls of capillaries to reach damaged tissue.

While red blood cells, carriers of oxygen, are part of the blood transport system, white blood cells are the passengers in it. When colds or other infections strike, CSFs are the body’s first response to invasion, immediately calling on cellular troops to marshal forces against the attack.

Scientists have identified several colony stimulating factors and each is genetically programmed to trigger stem cells deep in the bone marrow--where all blood components are manufactured--to grow and differentiate into specific types of blood cells.

Subject to Replication

But scientists, having deciphered some of the factors’ DNA codes, now can genetically engineer them in the lab in mind-boggling quantities, producing CSFs for the series of clinical trials under way to test the hormones’ effectiveness in people whose immune systems are suppressed by drugs or disease.

There are four known CSFs that boost production of specific white cell types:

G-CSF is for white cells known as granulocytes and M-CSF is for the white cells called macrophages. GM-CSF stimulates both types of cells and Multi-CSF, also known as interleukin-3, boosts the myeloid group of white cells.

So far, genetically engineered versions of G-CSF and GM-CSF have been tested in human subjects.

“We can now ask questions that never have been asked in medicine,” said Golde. “We can ask how high do we want the white count and actually reach that level.”

He and Dr. Jerome Groopman of Deaconess Hospital in Boston recently tested CSFs in 16 AIDS patients in whom they attempted to augment immune system components badly ravaged by viruses, bacteria, protozoans and the antibiotics administered to eliminate the infections.

Not Intended as Cure

CSF therapy is not intended to cure AIDS but instead bolster defenses against such opportune infections as rare cancers and pneumonia that often hasten the deaths of people infected with the immuno-deficiency virus.

The AIDS pathogen homes in on the white cells known as the T-lymphocytes, produced in the thymus gland. Such white cells are not the subject of CSF therapy.

In their investigation, Golde and Groopman tried to find the most effective dose of GM-CSF, administered intravenously over 14 days to see if bone marrow components could be stimulated effectively enough to boost the body’s disease-fighting white cells.

The four patients who received the lowest dose had a mean increase in white cells of 250%.

But the greater the dose, the researchers found, the higher the white cell count. In one patient, the count leaped from a mere 1,600 before administration of the drug to 48,000 by the end of the study.

“We can get a white count to any level we want,” Golde said. “We can manipulate it, increasing it proportionately--twofold, tenfold--and this with relatively low doses.”

Further Tests Planned

He said further tests with the genetically engineered hormones, which have produced no side effects so far, are being planned for other groups of patients with AIDS.

In an investigation of G-CSF at Memorial Sloan-Kettering Cancer Center in New York, Dr. Janice Gabrilove discovered dramatic improvements in white cell counts in patients undergoing therapy for bladder cancer.

Gabrilove and her team theorized before the study that infusions of G-CSF prior to chemotherapy would have a protective effect on the bone marrow that diminishes during cancer treatments, rendering the patient susceptible to infections.

In the same sense that CSF therapy is not intended as an AIDS cure, neither is it being tested as a cure for most forms of cancer. But doctors hope to improve outcome for cancer patients by protecting the bone with CSF therapy, permitting patients to undergo higher doses of anti-tumor agents.

Results of Gabrilove’s investigation showed white cell counts increasing by 200% to 1,200%, with respect to dose, and no appreciable side effects in any of the patients.

“In about 10 years this will probably be standard treatment in 10% of all cancer patients,” predicts cell biologist Ralph of Cetus. “The questions we’re now looking into are how many more can we identify and how can we harness them pharmacologically?”

Might Fight Leukemia

Philip Whitcome of Amgen, which is testing G-CSF in its laboratory, said the promising results in cancer patients were predicted in earlier studies with animals. And he thinks the recombinant version of the drug is so versatile that one day it might be used in the fight against some forms of leukemia.

“In leukemia you have the Peter Pan syndrome. He stayed young forever. Leukemia cells are like that,” Whitcome explained. At least in culture dishes, he said, G-CSF has the unusual capability of “pushing leukemic cells over the threshold to maturity.”

“That way, they (leukemic cells) can lead a normal life cycle and eventually die out,” he said.

Such therapy could give people with leukemia a chance to undergo a cancer treatment involving neither radiation nor chemotherapy because the G-CSF would restore leukemic cells to a normal growth cycle.

But even a glimmer of such hope is still many years down the road, Whitcome said.

UCLA’s Golde and his colleagues are testing GM-CSF in victims of aplastic anemia, a sometimes fatal depletion of blood-forming components in the bone marrow caused by exposure to toxic chemicals or radiation.

He will say nothing more than that preliminary results “appear very encouraging,” but he predicts that CSF therapies for all forms of bone marrow depletion probably will become the standard treatments by the mid-1990s.

Researchers elsewhere in the country are testing the effects of CSFs in patients with breast cancer, metastatic melanoma and sarcoma.

CSFs were first postulated in 1906 by a team of French researchers who described what they believed to be a hormonal role in the formation of red blood cells. But it was not until 1965 that Australian and Israeli scientists noticed that bone marrow cells of mice grew and differentiated in culture only in the presence of certain hematopoietic, or blood-forming, factors.

In 1977, Melbourne medical scientist Dr. Donald Metcalf isolated a CSF in a mouse and was followed seven years later by Dr. Judith Gasson of UCLA, who isolated GM-CSF, the first white blood cell forming factor found in human serum.

Amgen has developed a recombinant version of a CSF responsible for triggering production of red blood cells. The genetically engineered drug is expected to be approved by the Food and Drug Administration later this year.

Dr. David Robertshaw, chairman of physiology at Cornell University in Ithaca, N.Y., said CSFs in the adult act on the primitive, undifferentiated “stem” cells in the sternum, ribs and pelvis to produce red and white blood cells in the bloodstream.

“The blood is made up of many types of cells. But the stem cells are the originating type for all of the blood cells. They are genetically coded to become a red cell or certain kind of white cell,” he said.

Blood Replenished

CSFs of both natural or recombinant varieties home in on specific types of stem cells to replenish the kinds of blood cell required by the body in the constant death and replacement cycle of the cells.

“The applications are very wide,” insisted Golde. “Consider a situation in which someone is suffering from an overwhelming infection. We can now give them antibiotics to injure the microorganisms, then ameliorate the side effects of that treatment with CSFs.”

He said the protein molecules are nothing like the lymphokines interferon and interleukin-2, which bolster maneuvers of circulating lymphocytes in the blood. He said he doubts “that anyone really knows what interferon does.”

By contrast, CSF molecules “do one thing and one thing only,” said Golde: directly boosting the ranks of the immune system’s front-line soldiers in defense against toxins and disease.

“I had a hunch 20 years ago that they would be very important,” he said of CSFs. “Things like this really make you stop to think about the new era of medical therapy we’re entering.”

Said Whitcome: “This represents the first advance in man’s ability to regulate the immune response since Jenner and Pasteur. Antibiotics just augment; CSFs give us control.”