PI Perspective #17

December 1995     View PDF     En español

Immune-based Therapies

The field of immune-based therapies is moving forward, with new therapies in the clinic and a number of technologies now in large scale trials. Despite the number of new clinical strategies, there remains uncertainty over how to interpret results from these types of trials, because it may be unrealistic to evaluate these new approaches in the same way that traditional antiviral approaches are assessed. For example, if the goal of an immune-based approach is to augment or heighten immune function, immediate responses on viral load or CD4+ cell number may not be dramatic but a long-term clinical benefit may still be realized.

Large trials of longer duration may be necessary to determine if some of these strategies are useful in the management of HIV disease. A number of presentations from the Interscience Conference on Antimicrobial Agents Chemotherapy (ICAAC), recently held in San Francisco, summarize recent results of several approaches to modulating immune responses in HIV. These include studies of:

• HIV-IT, a gene therapy approach to augmenting the body’s anti-HIV responses,
• interferon-alpha n3, a new formulation of alpha interferon with less toxicities,
• transfer of immune responses from one individual to another, also called passive immune therapy,
• transfer of antibodies engineered to target cytomegalovirus (CMV),
• interleukin-2 (IL-2) in combination with a protease inhibitor.

Two abstracts on studies of HIV-IT, an experimental immune-based strategy, may provide a new piece in the puzzle of understanding immune response in HIV disease. HIV-IT, which is genetic material resembling HIV, was the subject of a 48 Hours episode resulting in increased community attention to the technology. This approach, in development at Viagene of Southern California, can be likened to a gene therapy method of delivering a therapeutic vaccine. The strategy is to offer the body a fragment of material resembling HIV, in hopes that the body will mount an immune response and begin recognizing and destroying HIV or HIV-infected cells more efficiently. One study evaluated different schedules of administering the injection, using varying quantities of the material and increasing the number of injection sites. By increasing the dose and number of injection sites, cellular responses against HIV could be increased. The second study affirmed that by administering HIV-IT, there appeared to be increases in the cellular immune response against HIV proteins. Interestingly, however, these improvements or broadening of immune responses against important HIV proteins had no affect on either viral load (HIV RNA or DNA) or on CD4+ cell counts. HIV-IT appears to be safe, with toxicities primarily limited to pain at the site of injection. It is unclear if heightening these immune responses will result in any measurable benefit. Because this is a first generation therapy, it may be that the impact of HIV-IT on cellular responses is not strong enough to have a measurable affect on the virus or CD4+ counts, or it may be that the particular cellular responses which are generated as a result of HIV-IT therapy are not key immune responses necessary to control HIV replication. Only further study will help shed light on the utility of this approach.

One interesting abstract on a new form of alpha interferon renews interest in this class of drugs as a therapy for HIV disease. Early studies of interferon-alpha were mixed, with some studies suggesting that increases in certain forms of naturally occurring interferon-alpha were correlated with disease progression and others suggesting that the administration of manufactured alpha interferon may be beneficial. Studies conducted through the National Institutes of Health seemed to suggest that interferon-alpha may benefit people with HIV disease, but toxicities were a limiting factor in the utility of this approach, with approximately 35% of people suffering from flu-like symptoms resulting in discontinuation of therapy. A company based in New Jersey, Interferon Sciences, Inc., has identified a form of the chemical which appears to have greater anti-HIV effect than the currently available product, interferon-alpha 2b, in test tube studies. The Interferon Sciences’ product, interferon-alpha n3, does not appear to have the same toxicities as the currently approved and available product. A small study shows that people receiving the interferon-alpha n3 did not experience the typical flu-like syndrome seen with interferon-alpha 2b, there were no documented liver, kidney or bone marrow toxicities and there appeared to be an antiviral benefit from the therapy. Interferon-alpha is a naturally occurring chemical, produced by immune cells, which is potently antiviral. Synthetic forms of interferon-alpha appear to decrease HIV replication in CD4+ (T-cells) cells by interfering with the production of certain key viral proteins, notably, gp120, which the virus needs in order to infect CD4+ cells. Moreover, interferon-alpha, in test tubes, completely blocks HIV infection of macrophages, another important immune system cell which is also impaired by HIV infection. The new form of interferon-alpha is being studied at Walter Reed Army Institute.

Another immune-based strategy, passive immune therapy, has been the focus of study for many years. Passive immune therapy involves taking plasma from people who are healthy, HIV-positive and have high CD4+ counts, and giving it to people who have lower CD4+ counts, or are experiencing symptoms of HIV disease. The thinking behind this approach is that there may be antibody responses which are beneficial in keeping HIV and perhaps even opportunistic infections in check which, as the immune system is disabled over the course of disease, are no longer as resilient. Rather than trying to ‘actively’ induce the body to mount an immune response, as is being attempted with HIV-IT, researchers are ‘passively’ transferring immune responses from people who are healthy to people who are more advanced in disease. Passive immune therapy has been successful in treating other diseases, including viral diseases, but data on its utility in HIV disease have ranged from dubious to downright confusing. Some studies suggest that passive immune therapy may delay the development of opportunistic infections and have a positive impact on CD4+ count, while other studies show that it has no impact on HIV disease whatsoever. Some researchers believe that the reason why these data are so mixed is because the level or amount of antibodies (called the antibody titer) being used in passive immune therapy approaches in HIV is far too low to have an impact on the disease process. These researchers cite other diseases where passive immune therapy has been effective and note that the amount of antibody used in those setting were many times higher than what is being applied in HIV. An abstract from the ICAAC meeting may support this claim. Certain antibody titers were measured prior to delivering passive immune therapy to people with AIDS. Two weeks after administering therapy people who received plasma with titers less than 1000 had undetectable levels of the transferred antibody. In contrast, people who received concentrations of antibody titers over 3000 had detectable antibodies after two weeks. This suggests that more frequent therapy, or much higher titers of antibodies, need to be included in strategies for passive immune therapy against HIV disease. Until this happens the field, while still in limbo, at least will have a direction.

Preliminary data on another passive immune therapy approach, involving the use of monoclonal antibodies (engineered antibodies which target certain pathogens) were discussed at length at the ICAAC meeting. Monoclonal antibodies to HIV, CMV and hepatitis are all being explored in clinical trials. Data from a study of MSL 109, a CMV monoclonal antibody, suggest that the antibody is well tolerated and further studies will explore the potential benefit of MSL 109 with standard CMV treatment. Research into the hepatitis B monoclonal antibody is still in very early stages of human testing and preliminary reports suggest that higher doses may impact the level of detectable hepatitis virus. Further studies will be necessary to see if these approaches will be useful in fighting infections common among people living with HIV. If this technology pans out, less toxic alternatives to managing CMV, and new approaches to managing hepatitis could improve the quality life of people living with HIV.

Perhaps the most interesting presentation on immune-based therapies were data from a study sponsored by the National Institutes of Health which looked at interleukin-2 and the Merck protease inhibitor, indinavir. The study involved people who had volunteered for previous IL-2 studies at the NIH, who either did not have a CD4+ benefit from previous IL-2 therapy or who were part of the control arm and had CD4+ counts less than 300. The study involved 36 volunteers who received IL-2 + continuous indinavir, IL-2 + indinavir administered only during the 10 days of the IL-2 infusion cycles, or continuous protease inhibitor alone. People receiving either IL-2 + continuous protease or continuous protease inhibitor alone had better CD4+ responses than those who received IL-2 with intermittent antiviral therapy. One participant, who had been on previous IL-2 therapy and experienced no CD4+ benefit, when given the Merck protease inhibitor (indinavir) with IL-2 had CD4+ increases from 226 to 1022. Another volunteer, on indinavir alone saw CD4+ rises from 185 to 1085. Because the CD4+ increases in both the indinavir alone as well as the indinavir + IL-2 arms were similar, CD4+ rises were attributed to the addition of indinavir. There was a trend toward greater increases in CD4+ in the IL-2 + continuous indinavir group, however. After 14 weeks on study, the mean CD4+ increase of the IL-2 + indinavir group was 185, and 83 in the indinavir alone group. By week 25 the mean CD4+ increase in the combination group was 200 and in the protease alone group it was 175. Increases in HIV RNA accompanied the infusion of IL-2, but after 14 weeks, viral load appeared stable, with the peak antiviral affect of indinavir occurring early, after one week on therapy. Side effects were predominantly attributable to IL-2 therapy, and included flu-like symptoms. The most common side effect of IL-2 was increased bilirubin. Another study, looking at sixty people with HIV whose CD4+ counts were greater than 200, compared IL-2 + antivirals (AZT, ddI, ddC and/or d4T) to antiviral therapy alone. The mean CD4+ count in each group was approximately 400. At month 10, the mean CD4+ count in the IL-2 treated group was 1000, by month 14 it had fallen to 800. After 16 months, there was a mean increase in CD4+ cells in the IL-2 group of 37, versus a decrease of 5 cells in the antiviral alone group. Future studies will look at IL-2 in combination with protease inhibitors and TNF-inhibitors, in hopes of controlling IL-2-related toxicities.

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