PI Perspective #38
July 2004 View PDF En
español
Cytokine Therapies: Harnessing the Immune System
Immune cells communicate through chemical messages. For example,
one chemical might direct cells to where they are needed to fight
off an infection. Another may make cells reproduce, cloning themselves
to build an army to combat a specific infection. These chemicals
are called cytokines.
Scientists have been trying to decipher the chemical language of
the immune system to learn how to harness it for use in the fight
against AIDS. This article provides a general picture of cytokine
therapy to date—approved therapies, those currently in large
studies, those entering studies in HIV soon and a glimpse at tried
and failed approaches.
Cytokines: the past or the future?
One of the great clichés of popular writings about medicine
is the claim that some products “boost the immune system”.
This is far easier said than done, nor is it always clear that the
goal, even in HIV disease, should be to “boost” any
aspect of the system. Just as often, the real goal may be to suppress
or modulate some aspect of the immune response.
Therapies designed to influence the immune system are called immune-based
therapies. The field of immune-based therapies (IBTs) is still in
its infancy, but not so new that the reality of IBTs is outside
the grasp of day-to-day use in the practice of medicine. There are
currently approved and proven cytokine therapies that are routinely
used by people living with HIV. These include cytokines like interferon-alpha,
granulocyte colony stimulating factor and erythropoietin-alpha.
Interferon-alpha (Infergen, Roferon, Intron-A,
Peg-Intron)
is a cytokine with broad antiviral properties. It has been researched
and proven useful in treating viral hepatitis. It is also used in
treating an AIDS-related cancer, Kaposi’s Sarcoma (KS), which
is triggered by human herpes virus 8 (HHV-8), also called KS Herpes
Virus (KSHV).
Interferon-alpha is most known in the setting of
HIV as a broad spectrum antiviral. While test tube studies show
some anti-HIV activity of interferon-alpha, studies in people have
been conflicting. Other facets of its impact on immune functions
are also being explored. For example, studies are underway to see
if its use can prevent diabetes. It has also been proven to be useful
in treating non-viral cancers, such as malignant melanoma. It is
available in standard and “PEG” (pegylated) forms. These
forms combine it with PolyEthylene Glycol, which stabilizes the
interferon and keeps it in the bloodstream longer, thus improving
its effectiveness.
Granulocyte colony stimulating factor (G-CSF,
neupogen, Filgrastim)
is used by people with low neutrophil cell counts (neutropenia).
Neutrophils are important in fighting bacterial infections. When
these counts are very low (below 750) people are at increased risk
for severe and potentially life-threatening bacterial infections.
Drugs to treat HIV and related conditions, particularly anti-CMV
drugs, can cause neutropenia. It has also been associated with HIV
disease progression. G-CSF mobilizes neutrophil cells and causes
them to reproduce.
Erythropoetin-alpha (epoetin-alpha, Epogen)
is used for treating mild-to-moderate AZT-associated anemia. Anemia
is a decrease in red blood cell counts. Red blood cells carry oxygen
throughout the body. Severe anemia is treated with blood transfusion.
Symptoms of anemia may include fatigue, dizziness, difficulty concentrating,
menstrual abnormalities and/or decreased sex drive. Anemia can be
caused by HIV, HIV-related conditions and/or by drugs used to treat
HIV.
The horizon
Interleukin-2 (IL-2, Proleukin)
Of the cytokines being researched in the setting of HIV, IL-2 is
the most widely studied and furthest along in development. Also
known as T cell Growth Factor, IL-2 stimulates CD4+ cells to reproduce.
An emerging body of research suggests that IL-2-stimulated cells
thrive better in the face of HIV infection than other CD4+ cells.
IL-2 induces increases in CD4+ cell count levels that far surpass
those achieved by any other therapy researched for HIV. Two very
large studies are underway to see if IL-2, in addition to anti-HIV
therapy, reduces disease progression and prolongs life. For more
information on IL-2, call Project Inform’s Hotline.
IL-2 is also being evaluated for its potential to
heighten responses to therapeutic HIV vaccines. A few small studies
are including IL-2 as part of acute infection and early disease
treatment and structured treatment interruption (STI).
The bleeding edge
Two cytokines are drawing increased interest from researchers for
their potential in treating HIV infection. These are interleukin-7
(IL-7) and interleukin-15 (IL-15).
Interleukin-7
A healthy adult will maintain a CD4+ cell count generally from 500–1,500.
What keeps cell counts from falling below 500 or from reproducing
out of control remains something of a mystery. When CD4+ cell counts
drop below normal ranges, other cells begin producing IL-7 (among
other things), which in turn stimulates CD4+ cells to reproduce
and causes the thymus (where new CD4+ cells come from) to produce
more CD4+ cells. Low CD4+ cell counts have been correlated to increases
in IL-7 levels in people with or without HIV (e.g. bone marrow transplant
patients, etc.) It’s theorized that the body produces more
IL-7 as CD4+ cell counts fall as a way to prompt the regeneration
of CD4+ cells to normal levels. For this reason it is believed to
be a potentially important HIV therapy.
The first human study of IL-7 is recruiting volunteers
in the setting of cancer. HIV researchers are watching this study
and will learn about dose, schedule and side effects that will be
further evaluated in HIV studies. While there is increasing interest
in using IL-7 for HIV, there are concerns about safety. IL-7 activates
HIV and particularly a very aggressive form of HIV, called syncitia
inducing (SI) or R4-dependent virus. It’s possible that this
concern could be lessened by giving IL-7 with anti-HIV medications.
Some research in animals suggest that short-term activation of HIV
by IL-7 might be a good thing as it may decrease the reservoir of
HIV lurking in resting cells. The major barrier to moving this research
forward is that no company committed to HIV research currently makes
a form of quality controlled IL-7 suitable for large human studies.
Interleukin-15 (IL-15)
appears to preferentially enhance CD8+ cell number, function and
survival in animal and lab studies. These cells are important in
cell-to-cell killing of virally infected cells. While IL-2 stimulates
CD4+ cells to reproduce, IL-15 stimulates CD8+ cells. Also, IL-15
appears to inhibit cell death caused by activation. Immune activation
and a cascade of activation-induced cell death are increasingly
believed to be part of the immune dysfunction of HIV disease (the
“sink and drain” notion that HIV simply kills billions
of cells each day is no longer widely held). Increases in IL-15
levels have been associated with better control of HIV infection,
though which is the cause and which is the effect have not been
clearly determined. An IL-15 study for treating HIV has been in
development for years and never materialized. The major barrier
to moving this research forward is that the company who owns IL-15
(Amgen) is not committed to HIV research.
Tried and failed and tried again?
Several cytokines have been looked at in the context of HIV. Interferon-gamma
enhances the function of cells that control mycobacterial infections,
including tuberculosis and MAC. It has been studied together with
anti-TB treatment in people with TB and HIV. It is also being looked
at as an adjunctive therapy to enhance vaccine effects. Early studies
suggest that low doses of interferon-gamma may control HIV whereas
high doses may promote HIV replication. Interferon-gamma, however,
is also associated with cell activation, which isn’t necessarily
a good thing. Over the years, increased interferon gamma levels
have alternately been described as both a good thing and a bad thing.
This point is important when considering the challenges of researching
cytokines. In the body, cells are producing these chemicals at very,
very small—nanomolar—concentrations and together with
other cytokines. The combination of cytokines, in varying concentrations,
elicits different immune responses. At low doses IL-2 preferentially
stimulates natural killer cells, while at higher doses, delivered
intermittently, it stimulates CD4+ cells to reproduce. When IL-2
is given at high dose daily it produces no appreciable effect on
CD4+ cell count. When it is given for five days every eight weeks,
the effect is profound and pronounced The challenge with cytokine
research is not merely to understand the various biologic functions
of the cytokine, but also how best to give the therapy to achieve
the desired responses.
Interleukin-12
IL-12 was researched in the early 1990s because it’s believed
to enhance cellular immune responses (the type of responses associated
with killing HIV-infected cells, as opposed to killing free virus
in blood). Results from small studies suggest it had no effect on
either HIV levels or CD4+ cell counts at doses that were tolerable.
Dosing and schedules of doses may not have been fully explored to
truly understand the potential of this therapy, however.
Granulocyte macrophage colony stimulation factor
(GM-CSF)
GM-SF was evaluated in a large study to see if adding it to anti-HIV
therapy would decrease risks for opportunistic infections among
people with more advanced HIV disease. While there were some interesting
observations of decreases of specific bacterial infections among
those receiving GM-CSF compared to placebo, the differences were
not significant overall.
Interleukin-10
IL-10 is an immune suppressive cytokine that suppressed HIV replication
in test tubes. One study in people showed no impact on HIV replication,
positive or negative when IL-10 was given at 1, 4 or 8µg/kg
daily compared to placebo. Another study suggested that IL-10 therapy
may decrease HIV levels.
Interleukin-4
IL-4 has been researched for activity against the AIDS-related cancer
Kaposi’s sarcoma (KS) and its impact on HIV was monitored.
At a dose of 1µg/kg daily IL-4 had no effect on HIV levels
and little to no impact on KS.
These are a handful of cytokines that have been
studied in the setting of HIV. While they failed to show benefit,
it may be that at different doses, given intermittently as opposed
to daily, or combined with other cytokines, they will one day be
researched again and show promise.
Conclusion
As research advances and tools are improved to understand the immune
system, more is being learned about cytokines. There is increased
interest in harnessing the language of the immune system to direct
its responses and improve health. This research holds great potential,
though the road to realizing it will likely be riddled with failed
experiments and confounding results. Cytokine therapy is not merely
a tool of the future—years from the grasp of our medicine
cabinets. To the contrary, several cytokine therapies are now routinely
used by many people living with HIV.
Furthest along in the research pipeline is IL-2. Answers about
the value of IL-2 in combination with anti-HIV therapy are expected
within the next 2–3 years. The hottest new tickets in the
cytokine town are IL-7 and IL-15. Although neither has made a debut
in studies of people with HIV, there’s not an immunology conference
in HIV where they’re not the buzz. Activist involvement is
needed to ensure these two therapies are researched in HIV.
A handful of other cytokines have been tested in HIV, with either
negative or confounding results. They may make comebacks as more
is learned about the language of the immune system and how it acts.
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