Shot in the Dark
Against the Odds, Immune-Based Therapies for HIV Slog Along
Industry "Leery"Despite more than two decades of research, there is as yet no approved immune-based therapy (IBT) for HIV infection. And while antiretrovirals continue to course through the developmental pipeline, relatively few potential immunologic interventions are dripping their way toward efficacy trials. This imbalance is partly due to an incomplete understanding of HIV's effects on the human immune system compared to our detailed knowledge of the viral life cycle. Absent this information, targets for IBTs are typically based on theories regarding pathogenesis and thus are susceptible to failure if a particular theory turns out to be incorrect. (By contrast, a new antiretroviral compound can be targeted to a well understood step in the HIV replication process.)
In addition, several IBTs (including Jonas Salk's ill-starred therapeutic vaccine candidate, Remune, and the bone marrow stimulant GM-CSF) have progressed to phase III efficacy trials but have failed to show clinical benefit, making industry leery of pursuing compounds that risk a similar fate. It is also difficult to assess the prospective market for IBT given that none is available, while there are years of accumulated data on the sales of antiretroviral drugs. Despite these problems, there are a variety of IBTs in development at the current time. Richard Jefferys prepared this IBT pipeline report for TAGline.
The advent of HAART has led to a resurgence of interest in therapeutic immunization, based on the idea that viral suppression and the attendant immune reconstitution may provide an opportunity to induce new and more effective T-cell responses targeting HIV. The primary goal of these products is to maintain better control of viral replication during HAART interruptions, thereby reducing dependence on drug therapy over the long term. Although this is certainly a desirable outcome, there is as yet no convincing human data showing that therapeutic immunization can improve control of viral load when HAART is withdrawn. Some researchers -- including French doyen of immunology Brigitte Autran -- are optimistic about the prospects for this approach, while many others remain profoundly skeptical. This area of IBT research has recently been invigorated by the involvement of two large pharmaceutical companies, Merck and GSK, who now have therapeutic vaccine candidates undergoing human testing.
Interleukin-2: Forgotten but Not GoneAnother category of IBTs is comprised of candidates intended to improve overall immune function as opposed to just HIV-specific immunity. The hardy perennial of this class of therapies is interleukin-2 (IL-2), which has been in trials since the mid-1980s. IL-2 belongs to a family of chemical messengers called cytokines that transmit signals between the cells of the immune system. Initially dubbed "T-cell growth factor" due its ability to induce T-cell proliferation, IL-2 is now understood to have more complex effects, including an unexpectedly important role in programmed T-cell death. Many studies have demonstrated that IL-2, administered either intravenously or subcutaneously, can increase peripheral blood CD4 T-cell counts in people with HIV infection. However, questions persist about the functionality of these IL-2-induced CD4 T cells, with one recent ACTG study finding that they did not appear to improve -- and may in some cases have diminished -- the response to a variety of routine vaccinations (such as hepatitis A vaccine -- see TAG's Basic Science Review, January/February 2003). Side effects such as fever, chills and malaise are also typically associated with IL-2 administration. Nevertheless, it remains possible that the CD4 T-cell increases associated with IL-2 therapy will lead to long term clinical benefit by delaying HIV-induced CD4 T-cell depletion, and this hypothesis is being investigated in two large clinical endpoint trials, SILCAAT and ESPRIT. Preliminary results from these trials should be available in 2005. An engineered and potentially less toxic form of IL-2 known as BAY 50-4798 is also under investigation in a phase I/II trial.
The New Interleukins: IL-7 and IL-15Studies are planned for two newer members of the cytokine family, IL-7 and IL-15. IL-7 studies in SIV-infected rhesus macaques have shown dramatic increases in peripheral blood CD4 and CD8 T-cell counts, without a concomitant increase in SIV replication. A phase I study is now in the works at the ACTG. IL-15 is a cytokine that can induce T-cell proliferation and enhance virus-specific CD8 T-cell responses in vitro and in rhesus macaques. Higher levels of IL-15 have also recently been associated with enhanced control of HIV viral load after treatment interruption in humans (see TAGline, November 2003). A pilot study of IL-15 administered to SIV-infected cynomolgus macaques was presented at the February 2004 Retrovirus Conference in San Francisco, with preliminary results indicating significant increases in CD8 T-cells counts. Analyses of IL-15's effect on viral load and SIV-specific immune responses are ongoing. Researchers at the ACTG are also hoping to move IL-15 into human trials in the near future.
This article was provided by Treatment Action Group. It is a part of the publication TAGline.