Immune Restoration Conference Plans Late-Stage Treatment Research
On the weekend of January 23, over 25 leading AIDSscientists from government, industry, and academia, and from as
far as France, Swedend Australia, attended the second meeting of
the "Immune Restoration Think Tank," held in Rutherford,
California and sponsored by San Francisco-based Project Inform.
(See AIDS TREATMENT NEWS #151, May 15, 1992, for information on
the first immune restoration conference, held last April in
Washington, D. C.) Funding was provided by Project Inform, with
the help of corporate and individual donations.
This event differed from most scientific AIDS conferences in
several ways:
* The invitation list included over 25 top scientists, all
but two of whom showed up. Names most likely to be known to our
readers include: Daniel Zagury, M. D., Robert Schooley, M. D.,
Robert Redfield, M. D., Thomas Merigan, M. D., Clifford Lane, M.
D., Robert Gallo, M. D., John Dwyer, M. D., (see AIDS TREATMENT
NEWS #164), and Nobel prize winner David Baltimore, Ph.D. Anthony
Fauci, M. D., was expected but had to cancel due to events in
Washington.
* Participants were asked to focus especially on developing
treatments for late-stage AIDS -- for example for persons with
T-helper counts under 50, who have often been ignored in research
and excluded from most clinical trials.
* The scientists were divided into four teams; two were
asked to create plans for developing the best treatments in 12
months, and the other two teams were given a 36-month time frame.
On the first day, they were asked to create ideal research
strategies as if there were no resource limitations; on the
second day, to plan for the real world.
* Project Inform is coordinating ongoing followup to (1)
document the research strategies which came out of the
conference, giving all participants a chance to make corrections
and sign off on the finished product, and (2) "market" the
recommendations to pharmaceutical companies, government agencies,
and others, to gain the cooperation necessary so that the
research can actually occur.
* The conference took place on the Northern California
estate of movie maker Francis Ford Coppola, who led the group in
theater exercises before the meeting to create an atmosphere for
teamwork, unlike the individualistic, competitive atmosphere of
most scientific meetings. (Coppola is developing a movie about
AIDS research; however, no filming was done at this conference.)
The details of the research directions proposed and the
consensus reached are currently being drafted for submission to
the participants for corrections. In general, the 12-month plan
focuses on progress in treatments already in clinical trials; the
36-month plan also considers improvements in critical
technologies which provide a basis for better diagnosis and
therapy.
[Note: some parts of this article, below, include technical
terms which are not defined here. Readers do not need to know
these words in order to understand the rest of the article. We
included them so that scientists and physicians will know what
was discussed at the immune restoration conference. We expect to
explain these terms and concepts in future issues of AIDS
TREATMENT NEWS.]
The 12-month plan will likely include development of:
* Antiviral strategies, especially laboratory and phase I
studies to determine the best three-drug combinations, then
six-month trials of these, measuring CD4 counts, viral
levels with PCR and other techniques, opportunistic
infections, and other indicators of efficacy;
* CD8 and CD4 cell expansion and transfer;
* Exploring antiviral activity of supernatant from CD8 cells
of asymptomatic seropositives;
* Adoptive cell transfer between identical twins;
* HLA-matched transfers;
* Passive immunity studies with IVIG, and with CMV
antibodies;
* Maximum opportunistic infection prophylaxis;
* Restoring cytokine balance (e.g., the current
pentoxifylline trials);
* Measuring effects of GM-CSF and M-CSF (macrophage colony
stimulating factor) on antigen presenting cell function in
patients;
* Monitoring results of thymosin-alpha with IL-2;
* Possible use of growth factors and gene therapy.
We intend to cover the 12-month plan in more detail, and to
look at the 36-month plan, when more information is available.
Interview with Jesse Dobson and Martin Delaney
The followup to the conference is being coordinated through
Project Immune Restoration of Project Inform, by Jesse Dobson,
Brenda Lein, and Martin Delaney. In early February AIDS
TREATMENT NEWS interviewed two of the coordinators about what can
be done to see that the research recommended by consensus of the
scientists actually gets carried out.
ATN: What came out of the conference, and where will it go
from here?
JD: We developed two plans, one for what we could do in 12
months, and another for 36 months, to find the best ways of
reconstituting the immune system of persons at a late stage of
HIV disease. The scientists divided into four teams -- two for
each time period -- and there was an amazing amount of overlap
between the groups, and agreement within each groups. All the
scientists pretty much wanted to do the same things.
Unfortunately it's not what is now being done.
We created steering committees to flesh these plans out:
what needs to be done, where it needs to be done, who it needs to
be done by, who it needs to be done to, and what lab tests are
required, to optimize our base of knowledge when it comes time to
write these protocols. Also we will coordinate with the FDA and
others -- there were FDA people at our meeting -- so that they
can prepare, so that when we come to them for approval they will
already know what is being done and why. There is also the
funding issue.
Once we have these plans on paper, with these names attached
to them, we have a product we can sell -- to the Clinton
administration, to Congress, to industry, to academia, to the
NIH. Hopefully, we can sell the idea of them working together on
this. We have to persuade the necessary parties to get the money
to do this, and the permissions from the FDA and others.
MD: The other challenge is that doing this work requires
integrated research, instead of segregated research. So much of
existing research is not about curing a patient or ending a
disease, it's about licensing a drug for sale, or a process. If
that happens to benefit a patient, great, but the research is
organized for commercial goals. But here, the object is an
overall biological outcome in the patient. And to make that
happen will, in many cases, require coordination with multiple
pharmaceutical products, multiple blood products or technologies,
and probably more than a single institution to bring these pieces
together. I don't know where that coordination should be
happening, whether the government should be capable of doing it,
but clearly it is not happening. So for the moment, we're just
going to do it.
ATN: What will be the administrative structure to bring
this about? Are these 12-month and 36-month plans for particular
clinical trials?
JD: Particular integrated approaches. Not just clinical
trials; for example, for CD8 expansion, there are several
techniques to optimize the growing of cells with the best
function. This kind of research can be done in a coordinated way
around the world: some people look at IL-2 and PHA, some at
adding IL-4, some could use anti-CD3 instead of PHA. These are
approaches the scientists thought needed to be investigated, but
many would be left uninvestigated if there is no overall plan,
since often there is no commercial motive.
ATN: For the ongoing initiative to make these things
happen, will Project Inform take this and keep running with it?
MD: The collective weight of this group will be used to
make it happen. If the policies and programs get blessed by this
list of over 25 people, including a Nobel prize winner and the
rest of them, it gives it an authority none of us have alone.
JD: We're just going to do the administration, keeping it
together, having steering committees which include some of these
scientists and others as well. For example, if a steering
committee concludes that a particular technology needs to be
done, and we need a particular substance to do it, and the
company that makes that substance is not particularly interested,
but their director of research used to go to school with one of
the scientists in this project, then that scientist will call.
We're going to play every angle we can to move it forward.
MD: That angle is already being played on the continuing
development of PEG-IL-2, because that has essentially been
blocked by Chiron's disinterest in the drug. But now we have
members of the committee weighing in on that process.
ATN: How did you set the tone for the weekend?
JD: The whole weekend was to first promote camaraderie, to
make the scientists feel like part of the group instead of
rivals, and also to promote creativity, as opposed to having to
promote their own particular approach. In everything we did,
those were our themes. Now we go to followup, let's go forward
together.
On both the creativity and the camaraderie, Coppola's
participation was unique, something we couldn't have provided
without somebody like him.
MD: He had some theater exercises; I think it was very
important for the atmosphere of the group.
ATN: How can people support this process now, in the
followup stage?
JD: I need help in monitoring what's going on, to do the
administrative followup, the faxes, the conference calls, the
flights to companies around the world to talk to them about
making their drugs or technologies available. The more assets we
have, the more we can do of whatever it takes.
MD: Not all the steps of this plan need to be done in the
same place, or even as part of a single plan. There are some
elements that, just by being publicized, may trigger the
experiments happening in other locales. And that's OK.
JD: As long as we know about them and learn from them.
Hopefully people will contact us to say that they've seen our
plan, and they're doing parts of it anyway, and to ask whom they
should contact to see that their information is coordinated.
And we need community volunteers for tasks such as
transcribing tapes of meetings, helping make phone calls, faxing
documents.
And we need support from people with scientific expertise.
I've been looking for that for a long time.
And we need political support. People with late-stage
disease have long been left out, and we're trying to get put into
the overall agenda. So we need your help in writing your
Congressperson, or the Clinton administration, or a
pharmaceutical company, whatever.
MD: One example of a need is getting the word out to people
with AIDS who have an identical twin. Work has already been done
with a treatment called adoptive lymphocyte transfer, with
considerable success. Now it's also being done at the National
Institutes of Health. But in the past, people have only heard
about the bone-marrow transplants, which have pretty much been
disastrous as a treatment for HIV. But this new approach, which
is much less invasive and appears to be much more successful, can
readily be done now for people with an identical twin. Recently
I spoke on this at a meeting of a church group, and there
happened to be someone in the audience who had a twin and was in
desperate need of just this. So we have already referred him to
where he can get the work done.
JD: Another important message to get out concerns saving
your own blood cells. In 36 months, people with 300 T-helper
counts now may be those with 50 T-helper counts then. There are
technologies being developed right now for cryogenic preservation
(freezing) of bone marrow and cells. It wibe much easier to do
cell transplantation with the patient's own cells than with any
others.
ATN: If somebody reads this and says, "I want this done,"
where do they go?
MD: We had plans to get this going after our last meeting.
They fell through when the company involved pulled out. Now
we're trying to work with other companies to set this up. The
scientists were just about unanimous in the value of that
technology if we could make it available.
JD: If this is to be made widely available, it will have to
be through a private organization, either a nonprofit or a
business. Government research programs could only do it for a
few.
ATN: Could this be done by existing blood banks?
MD: We want to see if the people who have parts of the
technology on hand could invest in the parts they don't have.
JD: The big problem is that most of the groups
sophisticated enough to do this process don't work with HIV-
positive blood, and you need to have separate facilities for that
(to avoid the possibility of an administrative mistake in which
someone is accidentally given HIV-positive blood). Also, there
is the expense of obtaining a programmable freezer. And you have
to demonstrate the ability to properly store and track the
samples.
MD: A task for us is to have an early meeting with the FDA
to talk through what the requirements will be.
ATN: We have to work together to get this on the public
agenda.
MD: Yes.
ATN: If it's potentially within reach, then it's easier to
get it on the agenda than if it's just an issue that people may
want to work on but there's no possibility that they could get it
done for themselves. It's too much to expect that people go to
Australia (where the only clinical trial is now under way) to get
this done. If we can find a way to do it even on a small scale
in this country, that would help a lot.
ATN: Before the meeting Dr. Dwyer (who is conducting the
cell preservation trial in Australia, and came to California to
attend the immune restoration conference) told us that he wanted
to talk with Dr. Redfield about combining his work with the work
on vaccines, so that you could educate the cells before freezing
them. Did anything come out about this coordinated effort?
MD: That's part of the plan.
JD: But if I were a potential donor now, I wouldn't wait to
harvest cells, but would want to go ahead now.
ATN: How enthusiastic were people at the meeting to
actually begin cryogenic preservation of one's own cells on a
larger scale?
JD: They are enthusiastic, but nevertheless realistic.
They're counting on us to come up with this product (the plans
with the scientists' backing) to sell, to push back some of the
barriers that they find when they try to work together this way.
The institutions, the patent rights, etc. lead to a system of
secrecy and rivalry that makes it hard to move forward. They are
counting on our leadership with their support for making the
system more flexible, to allow them to do this type of
coordinated research.
It will be important for the AIDS community to support us in
this effort.
ATN: You mentioned the Merck drug L661, an antiviral. How
did that come into this meeting on immune-based therapies?
JD: People thought that when we tested some of the immune
therapies in people, we would also want the best antiviral
possible. They recommended some laboratory and human testing of
combination antivirals. They expressed regret that L661 was not
available for the testing they wanted now.
MD: There is a human study going forward with the three-
drug combination of AZT, ddI, and nevirapine, the Boehringer
Ingelheim drug; the Harvard group reported at Amsterdam that a
similar combination with L661 (pyridinone) produced a
dysfunctional mutation (abstract # P. A 2450). But this study,
which has started or will soon begin, is only for people with T-
helper counts above 150. What we need is to also recruit a
cohort with lower T-helper counts, so we will also learn how well
the combination works in that group.
The group seemed to feel that the L661 would have been the
better drug in this combination trial (since it had been used in
the laboratory test), but it wasn't available because Merck
wasn't interested in playing ball in this study. We have to work
on Merck for that. [Note: Merck is doing other testing of L-
661.]
JD: The tat drug is another obvious one that we would like
to see in combination.
ATN: What did the scientists think of thymus cell
transplants?
JD: That's one of the 36-month plans. We need to know more
about how the thymus, and stem cells, and therapies for those,
have a role in immune restoration. The steps include doing a
workshop in bone marrow, studying autopsies of the thymus at
various stages of diseases which we don't have right now,
learning how to evaluate the state of the thymus without taking
it out -- things like that haven't been done. Also, looking at
the bone marrow at different stages to find what we can do. The
issues they identify are: how do cells reject these kinds of
grafts, how does the age of the donor affect the ability of the
cells to still be useful, using thymus cells from other people
and possibly from animals, and what kinds of T-cells do they
generate?
We also need to characterize the function of the cells, how
the growing process could optimize this -- and how the cells
could be grown to last longer when put into the patient.
Comments from Scientists
On the last day of the conference, five of the scientists --
David Baltimore, John Dwyer, Robert Gallo, Thomas Merigan, and
Robert Schooley -- answered questions at a press conference
organized by Project Inform. The following is from our recording
of that press conference:
Dwyer: I'd like to congratulate Project Inform for very
constructive activism here. Those of us who care for people with
HIV know how important it is to come up with strategies to help
people who have fairly advanced disease...There has to be
research on how to help those people. The excitement of being
with colleagues who all have something to contribute I find most
stimulating, and I think good things are going to come out of
this approach to science.
Schooley: What's most striking to me is the sense of what's
possible in the next 36 months -- if we can put the resources
together in an organized way, we could see major changes in the
next 36 months, if this is done right...In a meeting like this,
all the possibilities are thought of in a neutral way, and in a
way that in the long run people can integrate.
Baltimore: This meeting is the kind of thing that should
have been happening all along for the last decade. Maybe it
presages an attempt to evaluate the programs that have been going
on over the last decade, to put them in the perspective of the
disease as it affects immunity, and develop a more strategically
oriented research program for the Federal government.
Merigan: I think this is a product of a maturation of the
relationship between activists and investigators, rather than
necessarily government oversight. It's involving government,
industry, the people doing the studies, and the people who will
be studied. It's coming out of private, nonprofit support, and
that is exciting.
Dwyer: Yesterday we were invited not to be inhibited, to
put forward ideas that might turn out not to be practical. Today
we were asked to be more realistic. As we refined the
opportunities it became clear that the sort of collaborative
effort that is going on this weekend among scientists, that if we
don't get the same sort of enthusiasms for moving forward
together from regulatory bodies, from high-tech companies, from
drug companies that are working on a new drug, if they are not
prepared to enter into this same sort of collaborative spirit to
really accelerate practical research, then much of what we were
talking about today won't come to fruition. I would like to
think that our enthusiasm for this whole process will be
translated back to Washington, back to a number of the companies
that are involved in working on one small piece of the jigsaw
puzzle so we can put the pattern together that much faster.
Schooley: It is striking that yesterday we tried to develop
these 12 and 36 months plans without any constraints
philosophically on what we were doing; today was a supposedly
more targeted and practical discussion. But the actual plans we
came up with are not that different, which argues very strongly
that when we're thinking philosophically, when we're thinking
practically, we have the tools; it's just a matter of turning
ourselves loose to use them. If we can do that, we should have
major progress both in our approach to this disease, and also in
thinking about how we should approach other diseases.
Gallo: In the end, sometimes in the laboratory you're doing
work on pathogenesis and come up with an idea for something you
think is useful therapeutically, but we at NIH are limited by the
chance that the industry will be interested, or what is their
position on that approach, or is there a company that will drive
something forward and produce a product.
(Press): Do you have a wish list for President Clinton?
Merigan: The opportunity in biomedical research is
unprecedented now. And to have us constricting, and perhaps lose
our leadership as a country, is a real loss. The Clinton
administration will get a return in keeping alive one of
America's strengths if we do the right thing with this problem.
Dwyer: The socioeconomic costs to the country of not coming
up with solutions to this problem, as people require more and
more care, and it's expensive care, and in the most productive
phase of their life can't contribute in the way we would have
liked, those costs are staggering. Any money spent that reverses
those trends is a very cost-effective way to go.
Schooley: We are moving from an era in which all the drugs
have been basically of one class to an era with drugs of multiple
classes coming along, giving us an opportunity to combine these
drugs. Major new theories suggest ways of inactivating the virus
by using a sequence or combination of drugs in a specific
way...In 1985 and 1986, the average life expectancy of someone
who presented with pneumocystis was five or six months; we're now
five or six fold better than that, with the very limited tools we
have had in the last five or six years, one very limited class of
drugs, and focus primarily on one specific opportunistic
infection. With the tools being developed now, we might make the
same five or six fold improvement in survival. This is a time
for optimism. When you have these tools available and want to
apply them, to see the resources constricting is enough to drive
one crazy. This is the time to use all these tools and be
innovative...The focus of this conference was removing the
barriers that have slowed us down in the past.
(Press): What are your barriers?
Part of it is the culture in which we all work. At this
meeting we had people from government, people from academia, from
industry -- usually we don't talk together very well. We tend to
think about isolated projects, with individuals working on
specific areas, but we don't think about how to integrate that
into the overall picture, how to have resources flow in a rapid
way as we should, as new leads are developed, and how to
integrate the advances in one area rapidly in another.
(Press): Could the FDA help in problems with pharmaceutical
companies?
Gallo: I don't know if the FDA could affect that. It's one
of the real obstacles that there's not a clear solution to. You
can form collaborative research agreements very easily with
companies. But suppose our research indicates that a compound is
very important to go forward. Very often they're very
enthusiastic and it fits right in, and it's wonderful, and you go
forward. But if they' not enthusiastic, or don't have enough
capital at the time, or don't have the patent priority, that's
the problem.
Also, we have more administrative blocks now than when I
came to the National Cancer Institute in 1965. It was
significantly easier then than now for experimental testing, and
just getting clinical specimens. We've had new administrative
regulations and rules in the last three to four years; to get a
(blood sample) for any studies requires going through one or two
committees. To analyze a sample that comes from abroad is even
worse.
We've lost wisdom, balance, logic, for the sake of the rule.
The analogy I give is the sign that says don't step on the grass,
and a man is dying of a heart attack on the grass. I'd like to
see a committee to protect the scientists, that says you won't
get in trouble for using clinical specimens, because somebody
else will watch that.
Baltimore: The NIH is a remarkable organization for the
funding of basic research. It brings out the best that America
has to offer, it evaluates it very clearly, and it funds with a
reasonable sense of priority and expense. That's fine for
setting the base of understanding. It's not necessarily fine for
developing a focused program. In a focused program there are
real needs, and those needs may or may not be met by the existing
pluralism of the scientific community. There should be somebody
who can say that there's a hole in this puzzle that needs
filling, and go out and encourage the filling of that hole,
trying to find the very best people. That's an authority that,
as far as I can tell, nobody has in the Federal government;
certainly if they have it they don't use it.
The solution certainly involves having a strong figure at
the head of the research program, a leader who has the authority
of oversight over the whole research program. I think Dr. Fauci
has made a major contribution to the AIDS program and to American
research, but he is limited by not having authority over the
whole program; the programs are divided among various institutes
at the National Institutes of Health and they should be
coordinated together. There's a very great need for coordination
of industrial, university, and government activities, and we
should look at what it takes to do that. The notion of a czar is
just a word, the notion of a Manhattan project is a convenient
word, for saying that we ought to be looking at this in a
different way.
Merigan: But we have to maintain diversity, because this
isn't a problem that any one human being can structure
completely.
Baltimore: Look at the Manhattan project; it was the best
brains in physics getting together to solve a problem. It was a
pluralistic program from the beginning. Since they didn't know
exactly how things were going to end up working out, they started
down many different lines. You don't give up the diversity in a
focused research program, but you do have some sense of where
you're going and what it takes to get there.
Dwyer: The attractiveness of what we're doing this weekend
in a mini way, if it were expanded, is that you're likely to get
infinitely more return on the dollars you spend. You're going to
need more dollars, because what we're talking about is going to
require considerable resources. But you get more return on your
money by bringing together people who can cross-fertilize and
stimulate each other, and come up with the major holes in our
story that need to be plugged before we can go forward.
Merigan: A broad consensus of investigators and activists
coming together, and going in the same pack, can really move the
process when there is a barrier on the company side.
Schooley: When we are running a clinical trial we are asked
to test if this drug works. We as scientists want to know if the
drug works as well, but we also want to be asking about the
disease process at the same time. So whether the drug works or
doesn't work, we've learned something else about the disease,
allowing us to come up with more innovative and useful
approaches. But if the trial is sponsored only by a drug
company, and if within the company the interest is only to market
their drug, you don't have the resources to ask the kinds of
questions that will let you make the next leap. More and more
drug companies are seeing this, and realizing that their progress
will be enhanced by being able to ask these deeper questions.
This is not going to be a disease cured with one drug, but with
multiple approaches. As companies realize that they work
together; that's one of the healthiest things I've seen in the
last several years.
Note: If you can help in any way -- with contacts,
scientific or other expertise, volunteer office help, money, or
otherwise -- call Jesse Dobson or Brenda Lein at the Project
Inform office, 415/558-8669 on weekdays.
source: AIDS Treatment News
