Interleukin 2 (IL-2)

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June 2000 JulyNUMBER NINE

  SPECIAL REPORT

IL-2

A New Ally? An old drug performs new tricks.

by Bass

Today, a renewed emphasis on using the immune system to control HIV has led to novel approaches to restore and unleash its power, even if the virus has partly wrecked it. One strategy entails using an experimental drug called interleukin-2, or IL-2, to activate the immune system and essentially turn up the volume on the body's defense system.

IL-2, a naturally occurring immune booster, has been in scientists' hands since the dawn of the epidemic, but it hasn't found a niche in the arsenal of anti-HIV strategies until now. Although early clinical trials of the drug used alone proved disappointing, IL-2 is now the leading contender for adjunct immune therapy to highly active antiretroviral therapy, or HAART, a pairing aimed at restoring lost immune defenses in chronically-infected individuals.

The idea of immune stimulation is hardly new. One hundred years ago, ambitious physicians dosed cancer patients with bacteria, creating a microbial red flag they hoped would provoke the immune system into charging at everything in its path, including cancer cells. This crude treatment, which produced side effects worse than those of the disease itself, was soon abandoned.

When scientists identified IL-2 in the early 1980s, it seemed the ideal candidate to test on runaway tumors. The molecule, one of a family called cytokines, plays the role of a chemical messenger that allows immune cells to communicate with each other, and is responsible for a series of immune responses. Specifically, IL-2 triggers the division or expansion of CD4 T-helper cells, which have been called the conductors of the immunologic symphony. These helper T-cells provide a signal to CD8 T-cells, also called killer cells, to directly attack foreign invaders. IL-2's ability to boost cells was first tested by scientists who hoped to activate large quantities of tumor-specific T-cells against incurable cancers.

Researchers met with mixed results. While the drug proved moderately effective in reducing tumor growth, it was used in such high doses that it caused a condition akin to septic shock, which also produces massive immune activation, not unlike the 19th-century bacterial cures.

That didn't stop scientists from turning to the drug when it became clear that HIV disease was driven by the progressive destruction of the immune system, particularly CD4 T-cells. Cliff Lane, the current clinical director at the National Institute of Allergy and Infectious Diseases, started studying IL-2 in patients in 1983, as did others, hoping that their research would help tip the balance in the favor of the immune system.

There was every reason to believe that it would. If CD4 T-cells conduct the immune symphony, IL-2 is the baton, the tool that cues and modulates the performances of virtually all the key immune players, from CD8 T-cells to natural killer cells. Over time, HIV chips away at the overall size of the CD4 and CD8 T-cell pool, and interferes with these cells' ability to function. A dose of IL-2 sends the message that it's time for the players to start performing-dividing and, ideally, conquering-again. "IL-2 is the magic wand," says Jay Levy, a leading immunologist and professor of medicine at the University of California at San Francisco. "We believe that when you give IL-2 to people, there is a double effect [on CD4 and CD8 T-cell populations] - if you have HAART."

That's a big if. IL-2 trials that took place before effective HIV therapies came into being failed to show much real benefit in using the drug. Without effective antiretroviral therapy, immune cells are in a constant battle against the virus. In this situation, IL-2 simply offers the virus new targets by expanding the pool of T-cells. It may even worsen matters by triggering a burst of viral replication in HIV-infected cells that were previously producing little or no virus. More virus means even more trouble for the body's besieged defenses.

By quieting the battle between the immune system and the virus, HAART set the stage for safer, more effective use of IL-2. Over the past four years, several trials have documented the drug's ability to increase T-cell levels. Most recently, a French study called ILSTIM showed that after about a year of intermittent IL-2 therapy, individuals on HAART and IL-2 had roughly 70 more T-cells than those who were on HAART alone. All the participants had chronic HIV infection and had T-cell counts below 200 when the study began, leaving them vulnerable to opportunistic infections (OIs). Researchers projected that those on IL-2 and HAART would see their CD4 T-cell counts rise above 400 in about seven months; without IL-2, they calculated the same change would take about a year. This increase would put people out of the OI danger zone.

The regimen used in most studies, which costs roughly $10,000 a year, calls for five-day cycles of the drug every eight weeks. During the five-day period, individuals get two shots a day for a total of 15 million units per day of IL-2. This dose is still high enough to cause severe side effects, including high fevers, flulike symptoms, hypotension, and fluid retention. Advil, Motrin, and other anti-inflammatory drugs may alleviate some of these side effects, which all tend to subside once injections stop. "Once the T-cell counts are up, you start to pull back on the frequency of the cycles," says Lane.

Kendall , chief of immunology at Cornell University and the person who discovered the IL-2 molecule, believes a low-dose form of the drug may be the trick to countering toxicities. His patients give themselves shots of 2 million IL-2 units per day, with no interruptions. points out that CD8 T-cells need IL-2 to survive; without it, they die. The low-dose regimen, he says, maintains sufficient concentrations to sustain CD8 T-cells and does not appear to cause any serious side effects, even after five years.

Open Questions

When it comes to warding off opportunistic infections, having an expanded T-cell population is like money in the bank. The bigger the account, the better. Following this logic, the national French treatment guidelines now recommend that IL-2 be given to HIV patients with undetectable viral loads and less than 200 CD4 T-cells. So why isn't everyone waving the magic wand?

Although IL-2 produces great effects on laboratory markers like T-cell counts, there's still no hard proof that these changes translate into real-life results such as slower disease progression and reduced rates of opportunistic infections. "I do not think IL-2 is an established treatment, nor should it be viewed as an established treatment by anyone for patients with HIV disease," says Lane, who worries that the drug's side effects may outweigh its benefits. Ten percent of all patients on IL-2 show some evidence of thyroid abnormalities and may have to undergo thyroid replacement therapy.

Another worry is that the new T-cells might not work. HIV is known to cause defects in certain immune cells, and expanding defective cells with IL-2 is like filling a savings account with Monopoly money. Across the board, studies show that cells boosted by IL-2 include some that can fight other infections, such as tuberculosis and cytomegalovirus, but not yet HIV. More sophisticated tests are needed to fill in the picture.

Then there are the unknown consequences of immune activation. IL-2 affects many different cell types; its most severe side effects occur because it leads to the release of inflammatory cytokines, particularly from an immune squad called natural killer cells. Over the long term, all this stimulation might lead to autoimmune disease, in which the body begins to wage war against itself. So far, though, there's been no sign of this, even in patients who've taken IL-2 for several years.

Answers could come from Esprit, the largest, most expensive HIV trial ever conducted. Launched by NIAID in March 2000, the $43 million dollar trial will track 4,000 people, half on HAART and IL-2 and half on HAART alone. After five years, researchers hope they can say for certain whether IL-2 adds to the benefits of HAART. Esprit will enroll individuals with more than 300 T-cells. Even more data will come from a similar Chiron-funded trial that aims to enroll 1,400 people with fewer than 300 T-cells.

Critics say that even these costly blockbuster studies may not prove definitive. In this case, IL-2 may still be a drug that looks best on paper. In a recent interview in Science magazine, Jack Killan, director of the AIDS division at NIAID, acknowledged these concerns, saying, "A lot of people are skeptical about whether it will be possible . . . to sort out the cause and effect when people cycle through different treatments."

What's Ahead

Despite so many caveats, IL-2 is viewed as a crucial player in a new treatment paradigm. The new model proposes using HAART to control the virus and introducing IL-2 to boost immune cells, a strategy that provides the immune system with a period of rest and rehabilitation. Some researchers propose as the next step, socking the immune system with the virus again. Drug holidays, or "structured treatment interruptions" provide one way to do this. When the beefed-up immune system sees the virus again, it may be able to take control. This approach may not work immediately, but over time, it could theoretically provide better control after each drug holiday.

So far there are intriguing hints that this approach could work. Last fall caused a stir with a small study suggesting that IL-2 may help control HIV infection when patients stop HAART or go on intermittent therapy. In his study, nine people on HAART with undetectable viral loads were given continual low-dose IL-2. After an average of three months, they stopped HAART but remained on IL-2. They saw their viral load levels spike immediately, and then drop spontaneously to an average of 36,000 copies, suggesting some degree of immune control. In two out of three patients who went off the drug a second time, the virus increased gradually before leveling off at around 10,000 copies.

When looked closer, he found that both of the patients who controlled their virus when they went off the drug a second time had strong HIV-specific CD8 T-cell responses, the very type of immune response that's been seen in long-term nonprogressors with HIV. He's quick to admit that there's no way of knowing whether IL-2 provided the extra boost to CD8 levels; the increase could be due to HAART alone. But he remains optimistic that IL-2 is making a difference. If he's right, then IL-2 not only brings back overall T-cell numbers-a kind of blanket protection-but also restores lost immune responses, in this case HIV-specific memory cells, against the virus. While explores the best way to use IL-2, others plan to add therapeutic vaccines made of inactivated HIV to further jack up the immune system. "It's going to be very exciting," says UCSF's Jay Levy, who's studying HIV-specific CD8 responses in people on IL-2. "Our prediction is that CD8 activity is going to come back to a point, and then if you immunize, you'll see it come back dramatically."

The most important thing, researchers emphasize, is to keep helping the immune system flex its muscles. "The nice part is that if you talked to me five years ago about IL-2 immune therapy-forget it," Levy says. "The most refreshing thing is that people are looking at the immune system instead of hitting the virus on the head all the time and saying, 'That's all we've got to do.'"

  June 2000 July  Copyright © 2000

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  Last modified 09/26/2000HIV PLUS

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