The colony-stimulating factors G-CSF and GM-CSF were approved by the Food and Drug Administration in 1991 and then seemed to drop off the oncology map. But they are hardly has-beens; the molecules have changed the way oncologists treat some types of cancer, revitalizing the field of high-dose chemotherapy. Questions and issues remain about their use and effects.
G-CSF and GM-CSF, although often thought of and used interchangeably, have never been compared head-to-head in clinical trials. Many physicians use the factors outside the scope of FDA approval, sometimes in spite of studies that show little benefit, and sometimes because such studies do not exist.
Current research on the factors creatively harnesses their power to trigger blood cell growth, sometimes with results that were only dreamed of as recently as 10 years ago. Some scientists are also researching hypotheses that the overproduction of these factors, or abnormalities in the cell growth they trigger, may actually contribute to cancer.
"CSFs have had a major impact on the practice of oncology since their introduction," said Jeffrey Crawford, M.D., professor of medicine at Duke University Medical Center. The whole area of high-dose chemotherapy exists now because of these growth factors."
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Both G-CSF and GM-CSF have FDA approval for the mobilization of stem cells, to help recovery after bone marrow transplants, and as adjuncts to consolidation chemotherapy for some types of leukemia. G-CSF also is approved to prevent febrile neutropenia after chemotherapy, but not to treat the condition. Some still use it as a treatment, said John A. Glaspy, M.D., associate professor of medicine at the University of California, Los Angeles.
"There is evidence in pediatric populations that it does decrease hospitalization and length of neutropenia, but in adults that hasn't been the case," said Glaspy. "In adults, we don't use it enough to prevent and we use it too much to treat."
Crawford agreed. "There's some benefit for shortening [the duration of] neutropenia, but no big impact on clinical endpoints, so it's a cost issue and there's still controversy there."
According to Crawford, research is scarce into the similarities and differences between G-CSF and GM-CSF. "There are almost no studies comparing the two," said Crawford, who was a member of the American Society for Clinical Oncology Health Services Research Committee in 1996 when it "strongly encouraged additional clinical investigation that will . . . address issues of comparative clinical activity, toxicity, and cost-effectiveness."
Another obstacle for a wider embrace of CSFs is the need for daily injections. "Medicare doesn't pay for self-administered medications," explained Glaspy. "People have to come to the doctor every day for 7-10 days to get a shot" of G-CSF in preparation for stem-cell collection. Both Glaspy and Crawford are hopeful that pegylated G-CSF will soon be approved by the FDA. By binding polyethylene glycol (PEG) to the G-CSF, the factor remains in the blood longer, and patients can receive just one injection.
Cytokine Stability
While clinical issues remain, research into the CSFs continues. Jeffrey Malter, M.D., and colleagues at the University of Wisconsin, Madison, are studying what controls the production of GM-CSF and other cytokines. Their work centers on a specific untranslated sequence found in several hundred mRNAs, including GM-CSF mRNA. The sequence makes the mRNA unstable, causing it to degrade in 35 or 40 minutes.
"The idea is that this sequence can tightly control gene expression," said Malter, professor of pathology and laboratory medicine. "Once the GM-CSF is made and dumped out of the cell, it has tremendous influence on other cells and on the immune system as a whole. It makes sense that the cell would want the mRNA to degrade quickly so as not to produce too much."
Malter's group has cloned the binding proteins that interact with the sequence and is examining how they're attached to the cell surface. They have mutated both the stop and the start codon on GM-CSF mRNA; in both cases, the mRNA stabilized.
"Some of us believe that cancer is driven by overproduction of critical growth factors, and this would be one mechanism by which you could overproduce these factors," said Malter. "If you look in tumor cells, and this hasn't been done a lot, you see more mRNAs than you should and they last longer than they should."
Malter cites a study in which human lung tumors were examined for overexpressed cytokine mRNAs. "They found that something like 80% or 90% of tumors overexpressed," said Malter. "Where they looked, the mRNAs were stabilized."
A future application involves specific altering of mRNA stability according to a patient's needs. "If you could block cytokine production, one could envision application to organ transplants, any kind of autoimmune disease, some kinds of infectious diseases," said Malter.
Another group of researchers hypothesizes that abnormalities in the differentiation of neutrophils can lead to congenital neutropenia, myelodysplastic syndrome, and acute myelogenous leukemia. G-CSF plays a role in neutrophil differentiation.
David J. Tweardy, M.D., associate professor in the Departments of Medicine, and Molecular Genetics and Biochemistry at the University of Pittsburgh School of Medicine, and his colleagues found a naturally occurring form of the G-CSF receptor that does not cause differentiation; the part of the receptor that normally transmits the differentiation signal is missing. The group found increased numbers of these faulty receptors in three of six AML cell samples.
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Intriguing Model
"We have an intriguing model right now for how beta and alpha get recruited," said Tweardy, "and are trying to develop peptidal mimetics that inhibit the binding of alpha without affecting beta." Ultimately, said Tweardy, a mimetic drug could be used in combination with G-CSF in AML patients to induce differentiation of tumor cells.
Richard Jones, M.D., director of the Bone Marrow Transplant Program at the Johns Hopkins Oncology Center, Baltimore, and his colleagues are using both G-CSF and GM-CSF as agents of differentiation in clinical studies of chronic myelogenous leukemia.
Jones and colleagues have published research showing that at doses of G-CSF at which normal white cells proliferate, CML cells instead differentiate and die. According to Jones, GM-CSF serves the same purpose: the group has two ongoing clinical studies in CML where patients receive either a T-cell-depleted allogeneic or an autologous transplant plus GM-CSF. The researchers also are combining interferon and GM-CSF for CML treatment.
"It looks like you can enhance GM-CSF's differentation effect using interferon, and some anti-cancer drugs," said Jones.
Past studies have shown that tumor cells engineered to produce GM-CSF generate immune responses against cells of the same tumor type. Now GM-CSF is indirectly helping Pierre Triozzi, M.D., and colleagues at Ohio State University Medical Center, Columbus, in early-stage attempts at a different kind of vaccine that would harness the power of a patient's own immune cells.
Triozzi, associate professor of medicine, is completing a phase I trial of a cancer vaccine using dendritic cells, potent antigen-presenting cells that normally present vaccine antigens to the immune system.
"GM-CSF is almost absolutely critical for the generation of [dendritic] cells," says Triozzi. "It plays a role in their growth and differentiation, and in their ability to do this antigen presenting."
Souped Up
Triozzi's group is using GM-CSF to grow dendritic cells in the laboratory. The researchers then attach a peptide corresponding to part of the product of the ras oncogene, common in pancreatic, lung, and colon cancers. The "souped up" dendritic cell should cause the immune system to react against any cell expressing the peptide.
"We can effectively generate the cells," says Triozzi, "and they do have some activity as far as generating an immune response. We're also looking at different ways to administer them subcutaneously, intravenously, or directly into the tumor, and at other peptides. Most of our research has been on the practical aspects of it how to use peptides with dendritic cells."
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