Immune Restoration Conference: Interview with Martin Delaney of Project Inform

On April 25th and 26th in Washington, D. C., Project Inform
convened an invitational conference of about 35 leading
immunologists and other AIDS researchers, to focus on restoring
the immune system, especially for persons with T- helper counts
under 50. The scientists included Jean-Claude Chermann, Anthony
Fauci, Robert Gallo, Alan Goldstein, Daniel Hoth, Tom Merrigan,
Robert Redfield, Jonas Salk, Robert Schooley, Robert Yarchoan,
Daniel Zagury, and others less known to the public. Some came
from as far as France and Australia. Project Inform paid airfare
and other expenses with assistance from pharmaceutical companies
and other sources -- about $50,000 in all -- and provided the
organizational support. Jesse Dobson of Project Inform organized
the conference, and helped design the technical program.

So that participants could discuss freely, it was agreed not
to quote what people said, or to publish their specific data,
without their permission.

But most of those who are interested in this meeting and its
results do not need the specific numbers, but rather an overview
of what is most important, and in what directions the leading
research is moving. To make this information available quickly,
we interviewed Martin Delaney, co-founder of Project Inform, who
attended the conference as a facilitator. We asked Mr. Delaney
to start with a history of how this meeting developed.

[Note: The interview includes some technical terms and concepts.
These are explained in the glossary section, below. Also, note
that our own explanatory comments within the interview are
enclosed in brackets.]

History, Goals, Organization

Martin Delaney: "About two years ago Project Inform made an
internal decision to direct its research efforts on late- stage
disease and restoration of immunity...not out of any disbelief in
the virus, but because everybody else was working on that, and
there wasn't enough attention given to the immune-restoration
area. Our ongoing goal is to facilitate research in this area.
Over time almost everybody with the disease must confront the
problem of the damage done to the immune system.

"I first raised this issue in a talk at the community
programs of the 1990 International Conference on AIDS [in San
Francisco]. I challenged Fauci to help create a conference on
this subject by year's end. We urged the Institute of Medicine
program of the National Academy of Sciences, their Round Table on
AIDS [on which Mr. Delaney serves] to host the first conference
on immune restoration, a state-of-the-art review. We got that
done in December of 1990. Then we held a second program, with
some of the same people, in mid-1991 on disease pathogenesis. It
became clear from both of these meetings that people in this
field weren't talking to each other; just having them in the room
at the same time led to a lot of learning and creative thought
among them. So after that second conference we committed to
somehow continue this process; the Institute of Medicine was
addressing other topics at that time. But by that time we knew
who the key players were, in the U. S. and around the world.

"Later, when Jesse Dobson started Project Immune Restoration
[of Project Inform], creating a third immune restoration
conference was a natural task for him.

"Also, I had attended a think tank sponsored by the
Pediatric AIDS Foundation. They had been holding these meetings
for some time, originally to guide them on how to spend their
money. It was an informal setting, usually at a wealthy person's
home or a private screening studio. There would be
presentations, but mostly informal discussion among the people,
with an experienced facilitator guiding it. At the end of that,
they would try to decide collectively what the Pediatric AIDS
Foundation would fund next. That process was different from what
we had been doing at the Institute of Medicine."

JJ: So different from the ordinary way that grants are
awarded.

MD: "I think it's a brilliant way to do granting; I wish we
could do that with other foundation money, or with government
money. There's so much less bureaucracy, and a much clearer
sense of your goals.

"Our recent conference combined elements of what we saw at
the Pediatric AIDS Foundation with the Institute of Medicine
programs. We sent out the invitations, and to our surprise
almost everyone came. It's one thing when the Institute of
Medicine of the National Academy of Sciences invites you to give
a presentation; it's something else when a rebellious community
group invites you. We had to turn people away.

"We wanted people to be able to think freely, to be able to
make mistakes, to try out new ideas (they're not allowed to do
that, usually), and to sound off. So one of the commitments we
made is no direct quotations, no press, and none of the specific
data would be released.

"Some of the information, because it's on the leading edge
of the technology, is proprietary. There was a mix of people
from industry and government; they had to all agree to come
together with their pants down for this to work."

Research Directions

"Some of the researchers there said this was the first time
in their ten years of working with AIDS that anybody had asked
them to focus on the very late stage of the disease. They also
admitted that the scientists and the government people had always
been operating under the assumption that these people are written
off. We've always suspected that; this is the first time I have
heard them own up to it.

"But having said that, they then said, 'That's an
interesting challenge. Why is it all that different, say, from
bringing somebody back after a bone-marrow transplant with
cancer? It's not something that inherently dictates abandoning
the patient.' It was a new thinking process for them, to begin
looking at it in that way.

"Another general consensus that evolved among them,
comparing data from the seven different fields we looked at, was
that when people had gone down to the 50 or 100 T-helper cell
levels, there was far more resilience in the immune system than
any of them would have anticipated just a couple of years ago."

[Note: the seven fields referred to above are: cell line
expansion (including cryopreservation); gene therapy; passive
immunotherapy; soluble factors; stem-cell research; transplants;
and vaccines.]

JJ: Did they fail to find this resilience even lower,
around zero T-helper count, or had they just not looked?

MD: "They hadn't looked. They did not go that far with
their data.

"For example, one vaccine group had expected that the
therapeutic vaccines would only show benefit in the over 500 T-
cell group. As they extended it lower and lower, they began
seeing response and reaction as low as 200 T-helper cells, and
now they are going down to the 50 to 100 range. They're far
below the level where they thought they would see a reaction."

JJ: ACTG 106 [the earliest trial of ddC+AZT combination
treatment] surprised us.

MD: "Good example. The patients had a median T-cell level
of about 70 when they began the treatment, and those people
really moved up.

"And there was also a strong sentiment among the researchers
that response doesn't just mean more T-cells. Redfield (of the
Walter Reed Army Institute of Research) was strong on the skin
test as a test of functional immunity. This isn't the usual test
with the same several antigens each time. They've improved it
with a variety of randomly selected antigens. Otherwise, you
might just be sensitizing people to a few particular ones [when
the test is used repeatedly], rather than improving a general
response."

JJ: Could people obtain this test?

MD: "I think it would be a great diagnostic tool, if
physicians could have access to it. It gives you a functional
measure of whether your therapy is helping a patient or not.
Especially now, with the choice of three different antivirals, or
no antivirals, how do you know which ones are helping? I think
this test is done with a combination of commercially-available
antigens. Redfield was eloquent about why it is valuable,
instead of just looking at T-cells [to tell whether a treatment
is working].

"One of the great issues in AIDS is how to measure a
response to a drug. The government has finally agreed to T-cells
as a surrogate marker, but everybody knows there are many
exceptions to that -- for example, people with zero T-cells who
are healthy.

Collaboration

"Another major outcome was the opening of new research
collaborations among the group. It had never dawned on me that
as a result of this meeting, they would right on the spot make
some new agreements, but they did.

"For example, one group at the National Cancer Institute
agreed to work with the people doing the CD8 expansion with
Kaposi's sarcoma (KS) -- which is a natural.

"Before the conference, a representative from one company
confided to us that he was nervous. He said they had been beat
up or ignored for four years, because nobody would believe that
CD8 cells were important, or that you could expand those cells
once they were lost. But the next day he was one of the
highlights of the show."

JJ: It's hard to think that people are starting now to talk
to each other after more than ten years of the epidemic.

MD: "Why is it only now that these things are happening?
Why is it that these people didn't even come together before?
Project Inform is not the only foundation in town. It has taken
us six, seven years to get in a position where we had the money
and credibility to create something like this. Why hasn't this
been going on every six months since 1985? Why isn't the
government itself routinely doing it?

"Dan Hoth (director of the Division of AIDS of the National
Institute of Allergy and Infectious Diseases) met me for lunch
the week before, said he'd heard about the conference, and that
it was the kind of thing they should be doing. He asked, what
would it take to get him into the conference? Of course he was
welcome; but on a lark, I said you could start by giving us some
financial help. To my surprise, they were able to pay several
peoples' travel expenses; he did it in a day and a half. They
can do things in a hurry if they want to.

"Another collaboration: an Australian group is doing
cryopreservation of cell lines; that has immediate importance.
One of them is now talking with the CD8 expansion people, as he
has demonstrated that freezing the cells is viable, and when
they're thawed, they're functional. So by connecting his work to
that of expanding the CD8 cells, you give people the opportunity
to create their own cell bank, for use at a later stage of the
disease."

JJ: This fits with the work that just came out of Italy on
superantigens and selective cell deficits (of CD4, i.e. T-
helper, cells).

MD: "Another collaboration is that a leading U. S.
researcher wants to work with an Italian group which has been
working with thymosin, a thymic hormone. The Italians have
completed a three-arm study with AZT, vs. AZT and interferon, vs.
AZT and interferon and thymosin, and that study appeared to show
a rather dramatic benefit for the arm which included thymosin.
This might tie in to work with IL-2.

"Perhaps it is time to combine several such factors. No one
of these thymic hormones or cytokines is going to replace
everything that's lost. But some combination may be more
effective than any individual one.

"Another possible collaboration would be to combine vaccines
with thymic hormones or other soluble factors. The researchers
said yes, it made perfect sense. We pressed them, why not now?
One of the vaccine experts invited us to meet to discuss a
protocol for doing this; another was open to trying it later, but
not for his existing studies. A third pointed out that he is
already doing something similar, combining an antibody against
interferon with a vaccine. The purpose is to give a turn-off
signal to the immune response, so that overactivation doesn't
continue.

"On cell preservation (cryopreservation), discussions are
underway to create a nonprofit foundation which would develop
practical applications of the insights gained by Australian
researchers and the CD-8 expansion people. [Then people could
save blood or bone-marrow cells early in the disease. Later,
those cells could be used to grow many more (outside the body,
using special equipment). The descendents of the person's own
cells would then be injected to replace cells which had been
lost.]

"These things were not going to happen before that weekend.
You get something just by bringing these people together.

"There are other conversations going on, but we don't know
their outcome yet. These include the area of gene therapy. We
pointed out that all of these efforts so far seemed to be devoted
to the same thing, producing an internal antiviral response
(inside the cell). We asked why not also use gene therapy to
stimulate cell-line growth? The answer was, "Yes, we could do
that." One researcher asked us to contact somebody else who may
already be working on it. So they may connect, to see if the two
approaches can be combined into a single gene-therapy approach.

"There seemed to be a general agreement to focus on the
under-50 T-cell group. This was new to all of them; they agreed
that it could be done and should be done. We saw the redirection
of gene therapy to at least begin addressing cell-line
restoration. We had a heated discussion on whether so much
effort should be given to creating a better antiviral response,
if we are not sure that the disease pathology is caused directly
by the virus. Initially there was a reaction, We said no, we
agree that HIV is the trigger. But the question is, what is the
bullet?

"No one had a proven theory on how disease pathology
proceeds. The group concurred that we don't know. Many argued
that no disease has been conquered without first conquering the
triggering agent. But meanwhile are there other things that
should be done. Gallo said he thought it was very important to
shut down TNF production. That led in to the cytokines and other
approaches that could be addressed directly, with or without
addressing HIV. The antiviral response we get today with AZT,
etc. is significant and measurable. Therefore, why don't we see
a better result in people?

"We also had an intense discussion between two leading
scientists over methodology. One asked what are the concepts,
what are you trying to achieve, where are you trying to go? He
was very strong on big-picture thinking -- 'And don't trouble me
with the details.' Whereas the other will eat you alive on the
details, but may be blinded on the big picture, where he's going.
This led to intelligent discussions of the need for the different
kinds of methodologies, and what the payoff is -- along with some
admission about how neither side had been listening to each other
for a long time, and it was important that they do so.

"The meeting agreed to the continuation of the group as a
standing think tank on restoration of immunity in AIDS, with
regular meetings every six months. They agreed to work on the
transcripts of the conference, and to attempt to publish a report
on it in Science or Nature.

"We also talked about how these communication difficulties
seemed to be affecting science seriously. Should one of the
functions of the think tank -- in addition to the scientific
issues -- be to serve as a training vehicle for process, for
scientists to work with each other in ways they are unaccustomed
to doing? That's on the table; they have left it up to us to
decide who the core of the group will be. We'll probably keep
the big thinkers in, with some people coming to the meetings
depending on the subject matter.

"They made a pretty convincing argument that the immune
activation research does not contraindicate using a vaccine -- as
Montagnier and some others have suggested, fearing that
therapeutic vaccines might make things worse in the long term.
But the top vaccine experts at this meeting said there is no
evidence of that They have had people on vaccines for three years
or more, and there is no evidence of disease acceleration. The
opposite was being shown, that there is evidence of long-term
stabilization. Vaccines seem to be functioning as antiviral
agents, but safe, nontoxic ones.

"The roundup on the vaccine area was the commitment to
consider therapeutic vaccines for persons with lower T-cells, and
to combine the vaccines with soluble factors or antiviral
medications. We will meet with the U. S. experts to try to
develop protocols. In Europe, the problem is funding, as well as
scientific rivalries.

"On passive immunization [also called passive immunotherapy,
or passive hyperimmune therapy], we contacted the Veterans
Administration in New York, which has conducted a small trial of
infusion of plasma which is rich in anti-HIV antibodies. They
came to the meeting, but chose to talk about monoclonal
antibodies instead, feeling that that was more hopeful than the
plasma-transfusion approach. They are developing a number of
monoclonal antibodies. Jesse Dobson convincingly argued that
this approach should be accompanied by some kind of a diagnostic
test, where the patient's virus could be exposed to different
antibodies, to see which ones are most effective against it,
since people have so many strains of virus. They agreed to that,
at least to try to build a test around their antibodies.

"In the stem-cell research area there seems to have been a
shift in goals. There is now talk about commercializing stem-
cell technology as a delivery vehicle for gene therapy. Everybody
doing gene-therapy work needs a vehicle to deliver it. They need
some kind of a cell, and the more primitive the cell, the better.

"Our concern was where does that leave the original purpose,
which was to begin rebuilding the immune system with these stem
cells? That led to a debate about whether this approach could
work, whether you also needed a functional thymus gland or not;
immunologists are divided on that.

"The Australians said they would be interested in combining
stem-cell work with their thymic transplants -- given a break in
the U. S. discouragement of fetal-tissue research, however. They
will at least talk about this.

"The stem-cell people also implied that regulatory and
public-policy obstacles are being encountered against their
research, and that the impact of these obstacles might be a delay
in the planned human testing. That was hoped to begin this year,
first in a breast-cancer patient this spring. If that went well,
last year their plans were to try it in an AIDS patient by the
end of 1992. They seemed to imply that that's not going to
happen now, and that these obstacles are the cause of the delay.
We said that if they would put the cards on the table, we might
be able to help fight those obstacles.

"The stem-cell technology was created for the project to
develop the SCID-hu mice. Several years ago the goal was to set
up facilities to test hundreds of antiviral drugs a month using
these mice. But what we hear is that the company then became
more proprietary, less willing to share. Nobody ever developed
the large-scale use that was anticipated, and most of them said
it was because of the price (of the mice).

"Now you wonder if the same thing may be happening. The
stem- cell work evolved from that technology for the mice.
Researchers isolated human stem cells, and took bits of fetal
human thymic tissue, and fetal human liver tissue, and implanted
them in nude mice. The consequence of that was the generation of
a human immune system in a mouse.

"Initially the goal was to produce the mice for testing HIV
treatments. But soon it became obvious that this work could also
be the key to rebuilding an immune system in an AIDS patient; it
only took a few human stem cells to generate the whole system in
the mouse. The commercial efforts had seemed to be focusing on
doing that, but now there is more interest in commercializing the
stem cell as a delivery vehicle for gene therapy. Maybe now,
after a major recent investment in this technology by Sandoz, it
may be possible to do both.

"In gene therapy, we were struck by how far along it is --
farther than most people believe. Some of the groups at the
meeting claimed to have something virtually ready for human
testing; but they are very nervous about the regulatory and
policy obstacles. One group has a two-part gene therapy that
they think can shut off most viral replication in the cells. They
hope to get permission to move rapidly to human testing, building
upon the success of prior gene therapy experiments -- that gene
therapy can be developed like other treatments, and no longer
needs to be treated as something exotic. We will get behind them
on this, and see if some regulatory pressure could be released,
so they could start testing.

"Another U. S. researcher was urging the opposite approach
-- to go slow, for fear of a backlash if something went wrong
from a premature experiment. Researchers tinker in the
laboratory, and don't always feel the pressure to take their work
into human testing. We talked about the willingness to take
risks in the research process, and go forward. Some of them
agreed, and even thought it was important that they be reminded
of that regularly.

"The cell-line expansion got nothing but respect from the
group. Others wanted to collaborate. There was some discussion
about whether to expand all the CD8 cells, vs. expanding only the
CD8 cells which make the antiviral factor which Jay Levy talks
about, the cytotoxic killer cells which will kill HIV-infected
cells. At least the activists in the room thought there might be
a problem with the selective approach, because it banks
everything on combating HIV -- whereas the principal benefit seen
from CD8 expansion so far was an anti-KS effect, which probably
was not mediated through HIV. So wouldn't you want to expand all
the CD8 cells? There might also be cells specific to other
diseases. The evidence was that there was no harm from expanding
all the cells.

"The Australians reported that their thymic transplant work
had partly been put aside, because of a consensus reached at the
first immune research conference in 1990, that you wouldn't
accomplish much by doing thymic transplants without stem cells,
and at that time the stem cells were not available. In the
interim, the group has done the cryopreservation project,
freezing CD8 and CD4 cells for later expansion and use. They've
only done it with a few people, but apparently it has been
universally successful; the cells are viable after freezing, and
they can be stored indefinitely as far as is known.

"Some researchers asked why not expand the CD4 population
(as well as the CD8)? In the past, the stock answer to this
question had been that some of the cells were infected. But
that's only a small ratio of them. If you grow the cells, the
worst you could do would leave the ratio of infected to
uninfected cells the same, which would not hurt -- and you might
be able to do better than that by treating the growing culture
with antivirals. The immunology people agreed that this should
be done; although nobody decided who would do it. That's on our
to-do list.

"There was also a review of the bone-marrow transplant data.
That was a history of disappointment. For a while the treatment
seemed to show benefit; but then the growing cell counts would
hit a wall and collapse, usually within a year. The researchers'
explanation was that this must be happening because virus is
still there. We suggested that the problem might be due to other
factors suppressing cell growth, factors we haven't identified
yet. They said maybe, and moved on.

"On the soluble factors, we had presentations from Italy on
the thymosin study, from France on THF, and on IL-2. The IL-2 is
probably the most thoroughly developed data, most intensively
studied; it showed no evidence of boosting viral levels. [It had
been feared that this drug might do so, since it stimulates the
growth of T-helper cells, some of which are infected.] The drug
produces a "sawtooth" effect, with T-cell counts rising rapidly
after infusion of IL-2, then dropping again with time after the
infusion. But over time, the trend remained above baseline. So
it wasn't just moving cells back and forth, between the tissues
and the blood, as some were suggesting; the data seems to show
that there is some expansion of the population. IL-2 alone is
not the answer, but it may be a part of it.

"On thymic humoral factor (THF), a new study is being
unblinded this May, so we did not see that data; all we saw was a
summary of early phase I experience, which suggested that further
testing was warranted. The researcher is also seeing elimination
of live virus in the peripheral blood, using different culture
methods to test -- even at very low doses of THF.

"What is interesting about the soluble factors is that
they're all showing some activity. Then why not try them
together? None alone is enough by itself."

Simplified Glossary

CD4 cells. Often used loosely as a synonym for T-helper cells.
Some other cells also have the CD4 receptor, which is a protein
on the surface of the cell.

CD8 cells. Another kind of immune-system cell. It is widely
believed that these cells produce an unknown soluble factor which
inhibits HIV. CD8 cells also appear to inhibit KS.

CD8 expansion. Growing the patient's CD8 cells outside the body,
in order to inject them back into the patient as a therapy. This
treatment has been tested on only a few people so far.

Cryopreservation. Freezing cells (especially CD8 cells) for use
by the same patient later in the disease, in case the cells in
the patient have been destroyed or damaged.

Gene therapy. Adding new genes to certain cells (such as T-
helper cells) to make them immune to infection by HIV, or for
other purposes.

IL-2. A protein produced by the body which stimulates the growth
of T-cells. A genetically engineered form has just been approved
by the FDA for use in treating certain cancers.

SCID-hu mice. Mice born with severe combined immune deficiency
(SCID), which have been given a human immune system by
transplants of various cells.

Stem cell. A cell in the bone marrow which can grow into many
different kinds of immune-system blood cells.

Soluble factors. Certain proteins and other substances (e.g.
IL-2, TNF, alpha interferon) found in the blood. They may have
either helpful or harmful effects on disease progression.

Therapeutic vaccines. Vaccines used to treat a disease after
someone is already infected or ill (as opposed to prophylactic
vaccines, which only work as a preventive and must be given
before infection).

Thymic humoral factor (THF). A hormone produced by the thymus.
Recently there has been considerable interest, especially in Los
Angeles, in its possible use as an AIDS/HIV treatment.

Thymosin. Another of the many hormones produced by the thymus.

Tumor necrosis factor (TNF). A substance produced by the body,
but which is often harmful because it is found in excessive
amounts due to certain disease conditions.