Being Alive 1994 Mar 5: 8
An article in the December 10, 1993, issue of Science detailed a brand
new study of interleukin-12 (IL-12). I recently had discussions with
Dr. Gene M. Shearer of the Experimental Immunology Branch of the
National Cancer Institute, a leading IL-12 researcher and a principal
author of the Science article. I also talked with Dr. Michael DeBruin,
who is study coordinator of the first, small human study of IL-12 to
begin soon at Genetics Institute of Boston.
IL-12 is one of several interleukins, which are natural blood
proteins. Studies of IL-2, a cousin of IL-12, at Stanford University
have shown that IL-2 increases T4 cells, but also probably increases
viral activity because of the added T4s.
IL-12, produced by Genetics Institute, works in a different and
seemingly more sophisticated and effective way. Not only does it boost
T4s, but it multiplies natural killer cells (cytotoxic T8s) and
several other immune-boosting agents such as gamma interferon and IL-2
A major difference between the several "therapeutic vaccines" which
have been floating around for years is that most, such as the
gp160/gp120 vaccines, are aimed at producing HIV antibodies from
regular B-cells. A few have sought (not very successfully) to achieve
a "cellular" response by trying to produce killer T-lymphocyte cells
which are known to directly attack and kill infected T4s.
Dr. Jonas Salk's "Immunogen" vaccine, constantly tested since 1987, is
claimed to produce this cell-to-cell response, although the Salk
presentation in Berlin last year was not well received. IL-12 uses
this "cellular killer" approach.
Dr. Shearer of NCI's Immunology Branch told me IL-12 has so far been
tested on the blood of some 47 HIV+ asymptomatics. One test showed
IL-12 greatly enhanced immune system reaction to such culprits as
influenza virus. A similar group of healthy controls had a normal
immune response in every way whether or not IL-12 was mixed with their
Shearer added that "Genetics Institute will begin human tests as soon
as possible. In the lab tests, this is the most powerful immune
response modulator we have ever been aware of."
Dr. Tom Merrigan, head of AIDS research at Stanford, has predicted
that IL-12 would be part of a "renaissance" in immune therapy. "It's
a way to push the human host to have control over HIV."
Most all of the infected blood used so far in IL-12 lab tests came
from airmen at Lackland AFB in Texas. Dr. Shearer said this was
because these people had not yet had any HIV therapy, so the HIV in
the human blood, although it mutates naturally and is never the same
in different people, had not mutated or been affected by agents such
as the usual antivirals or other HIV drugs.
In fact, Shearer told me that the upcoming human tests at Genetics
Institute would at first use asymptomatics. But study coordinator Dr.
DeBruin of Genetics Institute told me the first tests to be done on a
limited number of patients will include not just asymptomatics.
"We will start quite soon, and we cannot use just the most optimistic
[completely asymptomatic] cases. Our hope is that this first small
study will lead to a much larger trial and, of course, the goal is to
show that IL-12 works in all patients. Plus, we must later try to seek
approval from the FDA if all goes well and it will require some people
with AIDS complications to convince the FDA."
DeBruin was upbeat but also quite cautious about appearing to seem too
optimistic. "There are more unknowns than knowns for human tests," he
added. He particularly mentioned a possible concern about stimulating
interferon with IL-12, and possible side effects. (I can relate to
that I did my own private study using AZT, ddI and five million units
of alpha interferon daily for three months and boy, did the interferon
make me sick.).
The first Genetics Institute study will be private and is filled.
DeBruin told me he cannot project whether or not it will later become
a national ACTG (AIDS Clinical Trials Group) study. I am a founding
member of USC's ACTG Community Advisory Board, which was one reason
why I wanted to investigate IL-12.
IL-12 was discovered by Wistar Institute of Anatomy and Biology in
Philadelphia and Hoffman-La Roche of Nutley, NJ. Genetics Institute
and Roche have cross-licensed patents on IL-12 and both are free to
test the drug world-wide. My own guess is that Roche will follow its
pattern of beginning studies in Europe.
Regarding IL-12 in a more technical sense, it has long been shown that
almost all HIV-infected people can control the virus for many years
and stay healthy before the immune system changes and begins its slide
downward toward a collapse and progression of AIDS.
According to a presentation Dr. Shearer and his colleague Dr. Mario
Clerici presented about 20 months ago at the Amsterdam Conference, it
is this slide that signals the beginning of the devastation of AIDS.
The early response to HIV, called T-helper type 1 (TH1) has a vigorous
and effective cellular response. But the next phase, often years
later, called TH2, involves the collapse of immune cells and a large
increase in antibodies which fail to halt the advance of AIDS.
IL-12, the scientists involved believe, may cause a large increase in
the cellular response that can create a new, much later TH1 response
which will be effective in restoring the immune system.
Shearer said, "Our findings imply that in HIV infection, a TH1
response can be restored by IL-12 (at least in human blood in the test
tube)." But he carefully added that until testing in humans is done,
"It is still unclear whether the immune system can be restored once
it's shifted its gears, or whether perhaps we can only take
asymptomatics and simply hold them there."
DeBruin said the IL-12 study is all but ready to begin and that this
first small human trial might be finished near the end of May. A few
cancer patients will also be involved, because in earlier research
IL-12 suppressed the growth of tumors in mice.
Who knows? Other promising HIV studies have struck out, but there's
something in me that has a little more hope for IL-12. Maybe it's just
12 years of frustration and bitter disappointments. Regardless, I'm
most pleased to see this and other recent developments focus on
something other than the usual pop-the-antiviral-pill approach.