IL-12 attacks tumors on two fronts, but can it win the battle?
Several years ago oncologists saw great promise in interleukin-2 (IL-2), a chemical messenger in the immune system that calls killer T cells into action. Once alerted, these cells seek and destroy unhealthy tissues in the body. Cancer, it seemed, simply failed to summon this response. So researchers suggested that injections of IL-2 might sic killer T cells on tumors. In clinical trials, though, IL-2 fell short of this expectation.
Now another immune messenger, interleukin-12, is raising hopes. Like IL-2, this molecule enlists the body's intrinsic cancer-fighting abilities. In addition, workers have discovered that it can stunt the growth of new blood vessels in solid tumors. Deprived of a blood supply, cancer cells cannot receive the nutrients they need to spread. Hence, some scientists believe that although IL-12 may not be able to cure cancer, it could potentially keep many forms of the disease in check.
The finding, from Judah Folkman of Harvard University and his colleagues, appeared in May in the "Journal of the National Cancer Institute." To test IL-12, the group placed tiny pellets of a compound known to promote blood vessel growth--a process termed angiogenesis--in the eyes of mice. Within five days, new capillaries covered the cornea. When the mice were given IL-12, however, the capillaries vanished. "This is the first description of the fact that IL-12 might have an adverse affect on angiogenesis," says Robert S. Kerbel of the University of Toronto.
In fact, IL-12 does not retard blood vessel growth itself but causes immune cells to secrete gamma-interferon, which stimulates the production of inducible protein-10. This recently discovered protein appears to be one of the most potent in a series of angiogenesis inhibitors identified since the late 1980s. Although the notion of starving cancer cells instead of killing them has been slow to catch on, clinical trials of eight drugs having that effect are now under way. "This kind of alternative strategy would have been unheard of 10 years ago," Kerbel observes. "But molecules such as IL-12 make it a reasonably attractive paradigm."
Part of the tactic's overall appeal is that it may enable physicians to avoid the problem of drug resistance. "Even when traditional chemotherapy initially succeeds, in most cases the cancer returns more resistant," Kerbel notes. "Cancer cells have a formidable capacity to develop resistance because they shuffle their genetic deck very readily." In contrast, the genes found in the endothelial cells of developing blood vessels are far more stable and would very likely build drug resistances at a much slower rate, if at all.
IL-12's charm is that it can stall angiogenesis AND stimulate the immune system. IL-12 even stirs up more immune activity than does IL-2. Both interleukins prompt the production of gamma-interferon, which makes T cells into the killing kind, but IL-12 does so earlier in the immune response. This timing makes an enormous difference, says Michael T. Lotze of the University of Pittsburgh Pittsburgh Cancer Institute. "IL-2 arms the warheads, sets the triggers and drops the bombs, but IL-12 is the ammunition factory."
Clinical trials of injectible IL-12 began in May 1994--one year before Folkman's group reported its finding. So far, Lotze says, the results look promising. Last month he launched additional clinical tests of an IL-12 gene therapy. In mice the intervention eliminated existing tumors and helped the animals reject new ones as well. Other workers are investigating whether IL-12 might ameliorate the symptoms of AIDS and hepatitis. "We have every reason to be excited about IL-12," Lotze states. Still, it will be years before anyone will know for sure whether IL-12 lives up to its potential. As Folkman is quick to caution, "Many things work in mice and not in people."--Kristin Leutwyler
SCIENTIFIC AMERICAN July 1995 Volume 273 Number 1 Page 24
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