Two events transpired Tuesday which suggest that when it comes totreating HIV-positive patients with interleukin-2, less is more. Highdoses can be toxic, low doses therapeutic.

The first occurrence brought two men with asymptomatic HIVinfection to the immunology clinic at New York Hospital-CornellMedical Center (NYH-CMC) in New York. There, they receivedsubcutaneous injections of IL-2 far lower than ever beforeadministered with therapeutic intent to an HIV patient.

On the same day, the Proceedings of the National Academy ofSciences (PNAS) came out with its current issue, dated Sept. 17,1996. It carries a report titled: "Rational interleukin-2 therapy forHIV-positive individuals: Daily low doses enhance immune functionwithout toxicity."

That paper's senior author is immunologist Kendall Smith, chief ofimmunology at NYH-CMC, where those first two subjects kicked offa year-long Phase II trial to test the efficacy of ultra-low-dose IL-2 inblunting HIV infectivity and rebuilding virus-trashed immunedefenses.

"This one-year trial," Smith told BioWorld Today, "is restricted topeople whose CD4 counts at entry are higher than 500. What we'redoing in that patient population is a randomized study comparing atriple-antiviral regimen _ AZT plus 3TC plus Merck's Indinavir _with and without adjunctive IL-2."

Each arm of the study will enroll 20 individuals, for a total cohort of40. "Our statistician tells us that, given the data out there on results ofthe triple antivirals alone, we should look for an additive effect of IL-2 on, first, the rate of disappearance of the virus; second, the rate ofincrease of the CD4 cells over time," Smith said.

Smith and his team identified, isolated and characterized IL-2, thefirst hormone found to regulate the immune system, in the 1970s and1980s. This cytokine works by binding to special receptors, whichSmith and his students discovered in 1981.

These receptors are the keys to the paradox of how low-dose IL-2plays the winning hand in the game of dosage high-low.

Smith explained: "It all relates to the structure-activity relationshipsof the IL-2 receptor [IL-2R], which we worked out over the course ofa decade or so. It turns out that there are two different classes of thesereceptors. One of them has a high affinity, so low doses and lowconcentrations of IL-2 will bind to them, and activate the immunesystem cells.

"The second IL-2R class," he continued, "has 100-fold lower affinity,consequently requiring 100-fold higher dose and concentration tobind."

Smith also pointed out that "at least an order of magnitude morecells, about a billion, have these lower affinity receptors."

Most of these immune system cells are of the variety called naturalkiller (NK) cells. When IL-2 binds to those lower-affinity receptorson NK cells, Smith went on, "they may make their own set ofcytokines, which are primarily the proinflammatory cytokines thatthen in turn activate monocytes."

That's where high-dose IL-2 ran into trouble.

"There are 2 billion to 3 billion circulating monocytes," Smith said,"and if they get activated, you set in motion a cascade of ever-expanding amounts of cytokines being released." These includeinterferon, tumor necrosis factor and other agents of clinical toxicity.

"So," he summed up, "if you keep your IL-2 doses andconcentrations low enough, that 100-fold difference in affinity allowsa favorable therapeutic-to-toxic ratio."

High-Dose IL-2 Caused Deal-Breaking Toxicity

Early last year, researchers at the National Institute of Allergy andInfectious Diseases (NIAID) tested high-dose recombinant IL-2 in aPhase II trial of 25 HIV-infected patients. (See BioWorld Today,March 2, 1995, p. 1.)

Six of the 10 subjects who entered the study with CD4 counts (indexof immune defense levels) higher than 200 had a 50-percent jump inCD4 cells, but accompanied by transient bursts of viral load.

The other 15, with initial CD4 counts of 200 and less, experiencedmore persistent virus activity and little immunological improvement.All 25 suffered unbearable toxic effects, including kidney and liverdysfunction, flu-like symptoms and whole-body edema.

The just-begun ultra-low-dose Phase II dose-escalation and safetystudy follows Smith's Phase I trial reported in PNAS, which aimed atfinding the optimal amount of IL-2 between the extremes of toxicityand lack of therapeutic effect. "We wanted to identify a dose of IL-2," he observed, "that would be broadly applicable, particularly toHIV-positive individuals who are asymptomatic and going to work,going to school, carrying out their normal daily activities. And wenow know that we can do that."

Sixteen people, 14 men and two women, took part in that six-monthstudy. The team explored three different doses. The lowest, 125,000international units (IU) per square meter of body surface, "didn't domuch."

The upper range, 500,000 IUs," Smith continued, "was clearly toxic,in that all the individuals to whom we gave it had chills and fever,muscle aches and malaise within three or four days of that dose. Sowe arrived at a middle dose of 250,000, varying 50 percent plus orminus in individual patients."

About half a dozen of the original 16 "are continuing on IL-2," Smithsaid, "and continuing to do very well. The other ones essentiallybecame lost to follow-up."

NYH-CMC received the recombinant interleukin-2 for its trials as agift from Amgen Inc., of Thousand Oaks, Calif. Smith said heconsiders that when additional immunological studies and clinicaltrials now under way or imminent are successfully completed, he willbe ready to recommend low-dose IL-2 for general use as add-ontreatment of HIV-positive patients, asymptomatic and symptomatic,along with standard triple-antiviral therapy.

He made the point that "Because the IL-2 doses are so low, a year'streatment would cost approximately $3,000." This compares with atab of $21,000 incurred in the recently reported high-dose study.

Given that cost factor, and the fact that patients in his trial readilyself-injected the hormone, Smith concluded: "Conceptually, low-doseIL-2 could be to AIDS what insulin is to diabetes." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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