The Bay Area Reporter - July 12, 1995
Mark Bowers, ACT UP/Golden Gate Writers' Team

Although current antiviral strategies are uniformly mediocre at controlling viral production, they are fairly well-known to most people. The immune-boosting strategies are less well-known, and more difficult to evaluate. Theories of what goes wrong in immune function as a result of HIV disease abound; many strategies involve augmenting certain subsets of the immune system in efforts to stave off disease or to repair damage.

One immune-based therapy may be IL-12, a cytokine (a chemical messenger) that has looked promising since 1989. Several studies of the effects of IL-12 have attempted to fit it into an immune restoration strategy in AIDS and also define its use in the treatment of cancer, malaria, and tuberculosis. As recently as last April, the Wall Street Journal was excitedly calling IL-12 a "magic bullet" and the National Institutes of Health sponsored a special meeting to decide just how to develop IL-12 as a therapy and as a vaccine additive.

Then, last month, one kidney cancer patient in a clinical study of IL-12 died, while 11 others were hospitalized with "adverse reactions." The cancer trial was immediately halted.

What went wrong?

Genetics Institute of Cambridge Massachusetts and Hoffman-LaRoche have been looking at IL-12 in kidney cancer for more than a year. Observers were disappointed that long-awaited safety and toxicity data were not released after the conclusion of Phase I studies of the potential therapy. Instead, the NIH heard all about IL-12's effects against bacteria, protozoa, fungi, worms, and viruses. When the unexpected death occurred, no one had any context to evaluate the cause: was it the IL-12, or the way in which it was made? What responsibility do drug developers have to release safety data before they proceed with wider testing?

It may be that proprietary interests are outweighing the needs of people living with AIDS and other life-threatening diseases. While competition between Genetics Institute and Hoffman LaRoche may speed research (because they both want the prize of licensure and FDA approval), neither company was willing to go public with their early safety and toxicity data for fear of giving a competitive edge to the other company.

Mediated vs. humoral

IL-12 has been in the limelight because of the current fashion of belief in the Th1 and Th2 patterns of immune response (Th stands for T-helper). Simply put, some cytokines are said to be associated with a humoral (antibody) response, useful in controlling extracellular infections such as protozoa and worms, while certain other cytokines are said to be associated with cell-mediated immunity, the kind that tracks down and destroys virally infected cells and controls some bacteria. A shift from one kind of immune response to the other has been known in mice for many years. It remains difficult to prove in human beings, although this has not deterred everyone from vaccine researchers to alternative therapy proponents from leaning heavily on theory to promote their products. IL-12 has been said to be the most powerful immune modulator yet discovered. Some researchers speculate that IL-12 will keep the immune system in a Th1 pattern of response, possibly delaying progression to AIDS.

Encouraged by early reports about IL-12, AIDS activists pressed for early testing of the cytokine in HIV disease. Single dose, dose-escalating studies of IL-12 started at San Francisco General Hospital in May 1994. This was primarily a safety and toxicity study, a necessary step before studying the cytokine as a potential drug for the treatment of HIV disease. The good news is that the toxicities seen in the kidney cancer study were not yet seen in the HIV-related studies. Multiple dose studies were scheduled to begin this month, but have been put on hold until more is known about what happened to the cancer patients and why.

Brenda Lein, Director of Project Immune Restoration at Project Inform, noted, "It's important that the community not evaluate immune-based therapies by the same criteria as antivirals. The history of IL-2, another cytokine currently being research in AIDS, shows that it took years of research before a useful dose and schedule for the drug was nailed down. We're bound to see difficulties as research proceeds into immune-based strategies.

"We're playing with a very delicate system that we don't know much about - but the urgency of AIDS requires that we move forward with imperfect knowledge. The real goal is to minimize the risks. The companies should be applauded for slowing down a little here."

Shelf life, half life, and death

Genetics Institute continues to study the toxicities that became apparent in the kidney cancer study, and notes that the way the drug was administered changed slightly - and the formulation of IL-12 itself changed - from previous studies. The formulation change was intended to increase the product's shelf life while not interfering with other properties, such as half-life and uptake of the product. By July 10, Genetics Institute had determined that the formulation was not responsible for the death during the study, and is continuing its investigation of the difference between the dosing schedule that resulted in the 11 adverse experiences and the previously uncomplicated dosing schedule. Dennis Harp of GI Corporate Communications said, "We still hope to continue with our planned study of IL-12 in HIV after we meet with the FDA, which will probably happen by the end of the month."

The future of IL-12 remains uncertain for yet another reason. There are many promising avenues of IL-12 research that would potentially benefit millions of people who suffer from malaria, leishmaniasis, or schistosomiasis, common in the Third World. Both companies have resisted developing the cytokine for these indications, fearing the economic downside of distributing a drug through the World Health Organization. IL-12 will need to prove effective and profitable against cancer and/or AIDS before it will be developed for other uses. Meanwhile, development of IL-12 remains stalled, even for lucrative markets.
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