TREATMENT ISSUES -- The GMHC Newsletter of Experimental AIDS Therapies; Volume 5 Number 3 -- March 28, 1991
Douglas G. Brust, Ph.D.

IL-2's Role in the Immune System

When a foreign substance like a virus invades the body, the immune system responds by producing and activating specific blood cells to destroy the invader or neutralize its effects. Lymphocytes, like T cells, are an important kind of white blood cell activated during such an invasion. In response to an infection, certain lymphocytes produce proteins (called lymphokines) which alert other immune cells of the invasion and prepare them to respond.

IL-2 is a substance released by activated T4 cells. Once secreted, IL-2 regulates the immune response by stimulating still more cells which work to kill the cells that are infected. The "immune-boosting" power of IL-2 provides the rationale for treating diseases such as cancer and AIDS with extra doses of the substance.

IL-2 has had some beneficial results in clinical trials with cancer patients (23). However, in initial AIDS and ARC trials, IL-2 has been somewhat disappointing (24). Although it is difficult to compare the results of these trials, one pattern has emerged: people with AIDS derived no clinical benefit from IL2 alone. Low doses of IL-2 did not increase T4 cell counts, as was anticipated, and although some reports noted enhanced activity of other types of immune system killer cells, the results were scattered and inconsistent. However, these are very early results, and the potential still exists for IL-2 to improve the immune function in HIV-positive people.

Treatment with IL-2 alone seems to be a double-edged sword. While IL-2's boosting effect on the immune system yields some positive results, the drug also stimulates cells that are infected with HIV and may indirectly encourage reproduction of the virus (25). The negative effects may be reversible when an antiviral is used in combination with IL-2. In any case, early studies clearly indicate that IL-2 cannot be used effectively as a single agent for immunomodulation therapy.

AZT and IL-2

A fruitful line of research may be combination therapy with AZT and IL- 2. AZT interrupts HIV reproduction and may counter the tendency for IL-2 to boost HIV activity. At the same time, IL-2 could work to enhance the immune system.

Two studies, one conducted at Duke University and the other at Stanford, suggest that IL-2 and AZT therapy in the treatment of HIV disease may be promising (26,27). It is important to note, though, that both of these studies were small and lasted only 12 and 20 weeks each.

The studies examined the safety and efficacy of combining IL-2 with AZT in asymptomatic HIV-infected subjects with T4 cell counts over 400. Subjects were treated with AZT (1000 mg/day) for eight weeks, followed by combined AZT and IL-2 therapy for four weeks. Patients received doses ranging from 100,000-one million u/m per day and 1,500,000-12 million u/m2 per day of IL- 2. The study conducted at Duke University finished with a final eight weeks of AZT alone. Duke researchers reported that levels of another type of white blood cell (natural killer cells), which may work against HIV, rose dramatically during IL-2 treatment in 70% of the subjects. These levels remained elevated in three subjects, after therapy was discontinued.

Both studies noted an increase in T4 counts during the IL-2 treatment phase, but this rise did not persist after treatment was stopped. The Stanford Team unfortunately discovered that new T4 cells generated during treatment with IL-2 did not function well. On a positive note, both studies presented evidence that AZT prevented IL-2's reactivation of HIV.

Toxicity

Even though we have natural levels of IL-2 in our body, extra quantities of it can cause toxic effects - - especially at high doses. Side effects seen in cancer patients include chills and fever, diarrhea, upset stomach, rashes, muscle and joint pain, blood abnormalities, depression, liver-function abnormalities, and irregular heartbeats (28). In general, these side effects are fully reversible when the drug is stopped. More serious toxicities from cancer trials include heart attack, severe bacterial infections, and capillary leak syndrome (a condition associated with severe low blood pressure, tissue swelling, and poor kidney function) (29).

In HIV-positive, asymptomatic trial participants, researchers found that IL-2 and AZT were well-tolerated. Side effects were limited to flu-like Symptoms, slightly lowered white blood counts, and a reduction in the number of platelets. It is unclear whether IL-2 toxicity stems from the direct effects of the drug or from chemicals secreted by white blood cells affected by IL-2.

IL-2 therapy has drawbacks associated with its method of administration. Because the kidney quickly flushes IL-2 from the blood stream, the drug must be infused continuously in order to reach desired levels (30). This infusion usually involves a catheter, a device providing direct access to the bloodstream, attached to a portable pump. Such a system is inconvenient and increases the chances of bacterial infections at the site where the catheter enters the body. To overcome this problem, researches have modified IL-2 so that it remains in the blood stream for an extended period of time. A trial of this modified form of the drug, called "IL-2-PEG," is being conducted in San Francisco. IL-2-PEG is injected intravenously, and participants are also taking AZT. Another less invasive, but potentially effective route of IL-2 administration is injection under the skin (subcutaneous injection). Trials of subcutaneously injected IL2 and AZT combination therapy are being conducted at Rockefeller University in New York; contact Hedy Teppler at (212) 570-7794. Another trial at Duke University trial includes a hospital stay which is required of all participants; contact John Bartlett at (919) 684- 8111 ext. 5260.

The National Institute of Allergy and Infectious Diseases (NIAID) is beginning a study of IL-2 in combination with alpha interferon in people at all stages at HIV disease. A hospital stay is required for participants. For more information call Susan Haneiwich at (301) 402-0980 ext. 403. Additionally, researchers at Duke University are studying the possibility of boosting immune function in HIV-infected people by a therapy known as "leukophoresis." During this experimental procedure, blood is removed from the body, specific immune system cells are stimulated by exposure to IL-2 and then the immune enhanced blood is infused back into the patient. For more information call (919) 684-8111 ext. 5260.

Conclusion

Studies of the safety and efficacy of IL-2 in HIV infection are clearly in their infancy, though more than three years of federallyfunded clinical research has been conducted. It is extraordinary that we still have so little information about IL- 21s role in HIV infection. The first AIDS patient entered a NIAIDsponsored clinical trial of IL-2 on December 8, 1987. Today, four studies of the drug are being conducted by NIAID -- they are all phase I, dose-escalation trials. Only after a large, phase II, efficacy trial is accomplished will we know if IL-2 is helpful in the treatment of HIV-infected individuals.

Footnotes: 22 Inter-Sci Conf Antimicrob Agents and Chemo, abstract #110, 1989.

23 Rosenberg 5A et al. New ap roaches to the immrnnotherapy of cancer using interleu in- 2. Ann Intern Ned 108:853-864, 1988.

24 Schwartz DH et al. Interleukin-2 in the treatment of HIV disease. Biotherapy 2:119-136, 1990.

25 ibid.

26 VI Internat Coat on AIDS, abstract S. B. 421, S. F., June 1990.

27 VI Internat Conf on AIDS, abstract S. B. 444, S. F., June 1990.

28 Klempner MS et al. An acquired cbemotactic defect in neutrophils from patients receiving interleukin-2 immunotherapy. NEJM 322:959-965,1990.

29 Snydman DR et al. Nosocomial sepsis associated with interleukin-2. Ann Intern Ned 112:102-107,1990.

30 Schwartz DH. Interleukin-2 in the treatment of HIV disease. Biotherapy 2:119-136, 1990.

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