Today in Cardiology convened this round table in
November at the American Heart Association Scientific Sessions 2006 in Chicago.
Chief Medical Editor Carl J. Pepine, MD, moderated the discussion. Part
one of the round table is presented here. Part two will be published in the
March issue of Today in Cardiology.
Carl J. Pepine, MD
Scholar, Professor and Chief, Division of Cardiovascular Medicine, University
of Florida, Gainesville, and Chief Medical Editor of Today in
Brian H. Annex, MD
Director of Vascular
Medicine and Vice Chief, Division of Cardiovascular Medicine,
Robert D. Simari, MD
Professor of Medicine and
Chair of Cardiovascular Research,
Mayo Clinic, Minnesota
Douglas Losordo, MD
Medicine, Director of the Feinberg Cardiovascular Research Institute and
Program in Regenerative Medicine,
Northwestern University Medical School
Douglas Vaughan, MD
Amit N. Patel, MD
Director of Cardiac Cell Therapies at
McGowan Institute for Regenerative Medicine, University of Pittsburgh
CARL J. PEPINE, MD: Were here to discuss a very
interesting and important emerging therapy, cardiovascular cell therapy. What
do you think is the next most pressing phase of this field? Should we be
concentrating on the preclinical area to learn more about mechanisms? Are we
behind the times, particularly in this country compared to Europe, to take this
ROBERT D. SIMARI, MD: It clearly is a time that puts us as
a country behind Europe, Asia and South America in terms of cell therapy,
mostly because of the regulatory and funding issues. Unlike gene therapy, which
clearly had a much more rapid translation in the United States, we are behind
in the translation of cell therapies. And the question is, are we going to
catch up? Are we going to leapfrog, or are we going to bypass whats going
on in Europe? And what will we take from that? I think the answer to whether we
should be preclinical or clinical, the answer is yes. We should be both.
BRIAN H. ANNEX, MD: I agree with Rob. It is really
important that we recognize that translational research is not unidirectional.
Translational research is not merely taking what weve learned from the
lab and moving it into patients, but also understanding what were
learning from patients and bringing it back to the laboratory. So, I think both
of them have to continue in parallel.
This is a field that has enormous promise but also some potential
downsides that we have to be aware of as we move forward.
DOUGLAS VAUGHAN, MD: I cant disagree with whats
been said so far, but I think the real point is, that there has to be a really
deep and comprehensive dialogue between the communities that do the preclinical
research and the clinical research so they can share information and move the
field together because its not going to happen unless theres a kind
DOUGLAS LOSORDO, MD: Its a time of great promise and
that adds enormous burden of responsibility when theres this much
expectation, especially in the community. I think its our job, to a
certain extent, to control the conversation and make sure that peoples
expectations are realistic, that the timeframe of those expectations is
realistic, that the clinical trials which I think have to happen in
order for us to begin to learn about the potential and the potential pitfalls
are designed based on good preclinical science and that when data emerge
from those studies its interpreted very conservatively and that
I would add a third community in addition to the ones that Doug
Vaughan mentioned. [The lay community] has to be engaged here so that they are
brought along with this conversation and understand what it is that were
attempting to do.
PEPINE: Amit, youre the only surgeon on our panel. What
are your thoughts?
AMIT N. PATEL, MD: A lot of people feel we are behind
compared to Europe and other countries, but in reality, we can learn from what
they found and actually leapfrog ahead. So, some of the more bland or
equivalent trials that they have found, we could actually use that to our
Its not just as were looking at what cell type to use,
but really identifying the optimal patients where we can safely say this is a
patient that may potentially benefit from cell therapy. Conservative optimism
would be the right way to look at how to approach this as opposed to just the
extremes that you hear from South America or Asia, or the extreme conservative
views that we might get here in the United States.
PEPINE: Doug brought up the community and, speaking as a
clinician, what should I tell the patients that are telling me theyve
read about it on the Internet? They can go anywhere in the world, and they ask
if they should go to Thailand or Singapore or elsewhere and get a new
heart from their own cells? How do you respond?
PATEL: We get patients from around the United States and
other parts of the world who will read something on the Internet. Theyll
bring in printouts of vast amounts of information and thats all it is.
Its information and its our job to really decipher what they have
and tell them the reality. They may not be false promises, but theyre
unproven promises that based on their disease when we evaluate them, could
often benefit from standard medical care. Theyre just under-managed in
the current environment that theyre in.
So, we actually see more of that than the kind of dreams of magic
cells that are going to cure everything. Often, standard medical care actually
helps them out more than something thats still unproven.
PEPINE: Thats a good point. Optimizing guideline-proven
care could benefit all of these patients.
We seem to have a general agreement that we should move forward
into the clinic and keep the preclinical work going.
If we go into the clinic, whats your best guess as where
we should concentrate? The coronary circulation, the peripheral vasculature, or
somewhere else as a proof of principle in men?
ANNEX: The peripheral vasculature offers a number of
advantages: ease of administration, the ability to do repeated measures,
repeated administration and a number of efficacy readouts. I would caution, of
course, that the leg and skeletal muscle in the leg is very different from the
heart. The repair capacity of skeletal muscle is far greater than that of
cardiac muscle. I think at this point, if the preclinical data are in the area
of the myocardium, it should be moved appropriately and safely into the
myocardium where the studies have been directed toward peripheral vasculature.
I think thats an equally viable option.
LOSORDO: It will depend a little bit on cell type, disease
target, and what you seek to learn by a particular study. For example, in an
early phase study where perhaps you want to accumulate some safety and
feasibility data, then peripheral circulation, peripheral vasculature, offers
an easy target and something that has not been approached much yet in the field
of cell therapy.
Especially important when we think about regenerating or reversing
a disease process thats decades old is the possibility of
readministration of the cell. Again, [this is] much easier to do in the
periphery than in the myocardium.
On the other hand, the myocardium offers some advantages in terms
of precise endpoints that can be measured; for example, the use of MR for
assessing perfusion and regional function, which is very difficult to do in the
legs. Also, the relatively smaller volume of tissue of the heart offers the
advantage of potentially being able to administer close to a therapeutic dose
in a single administration, whereas in the legs it might be a bit tougher.
SIMARI: I think all three scenarios are very reasonable and
should be pursued, but I think the key question is what are we asking cells to
do and do they have the capacity to do that? How many leaps of faith, including
delivery, survival, maintenance and activity in the tissue, do we have to take
to achieve some sort of strategic goal? Im in favor of making as few
leaps as possible as early as possible, asking cells to do something that we
have enough evidence to believe they have the capacity to do in a timeframe
that we have the capacity to do it in. So, I think the fewer leaps or the fewer
hurdles that we have to achieve with these early studies, the better off
ANNEX: But you really want to have the outcome measures and
the endpoints. Essentially you want to design these almost the way you do
preclinical studies, making the steps from preclinical to clinical as small as
possible so you could answer the questions in the most definitive ways.
VAUGHAN: Theres a big difference, however, in terms
of what the strategy is when you talk about the peripheral vasculature and the
heart. In the heart were talking about generally trying to improve
contractile function somehow. In the peripheral vasculature, were talking
about restoring or rebuilding a vascular network or blood supply and, although
that may be part of what goes on, in the myocardium it might be part of the
goal there, theyre not completely overlapping in terms of what
youre trying to accomplish.
PATEL: For cardiac disease, you can pretty much break it
down into three strategies of use. In the acute MI patients, when they use
cells, we were hoping that maybe you could potentially reduce your infarct or
rescue the peripheral ischemic myocardium. In the chronic angina or some of
what is perceived as the low-lying threat, these patients are maximally
revascularized, [on] maximum medical therapy. Those are very definitive
endpoints in that group. If you have angina, does the angina reduce? Does the
medication usage decrease?
Actually what a lot of people hope for is the magic increasing
ejection fraction because when we deliver these cells, thats the biggest
issue. All these routes that everyone takes, whether its intracoronary,
coronary sinus, endocardiac, epicardial, the retention of cells is so low that
its very difficult to say realistically that when you translate from our
preclinical studies to humans that sometimes youre looking in the
neighborhood of only 3% to 10% [retention] of the cells. Its very
difficult when you see, not only in the lay press but in the academic journals,
these huge leaps of clinical improvement and you know [that] when you go back
and try to reverse-translate that into the animal models, most of these cells
dont stay in the cardiac tissue, let alone live for more than a week or
couple weeks at best.
PEPINE: But if the major mechanism of benefit is a
paracrine effect, would you agree that the cell may not need to
permanently reside there or be alive?
PATEL: Thats only partially true. If you say that,
then you are assuming that that cell is only producing one specific factor.
Whereas, if you take the cell as something more intuitive in the sense that
when you deliver it to the region of the heart which needs either oxygen
or muscle contraction then if it senses its local environment and, based
on that, produces the right substance of growth factors and other signals to
recruit other cells, then thats significantly more important than saying,
well, even though the cell died, it did more than something that just
released one factor. It interpreted its microenvironment and released the
appropriate factors before it passed away.
PEPINE: If we were going to go to the heart and talk about the
peripheral, what would you use or what would you start with as a cell
LOSORDO: I think you have to go back to the preclinical
studies that have been done and try to interpret them to get some clues about
what a reasonable starting point is. Also, our work is funded and focused on
endothelial progenitor cells and, as Doug [Vaughan] mentioned, that therapy has
really been designed to restore the microcirculation in the heart and to a
certain extent in the peripheral vasculature. But there is now really a 10-year
history of preclinical data to suggest that the [endothelial precursor cell
(EPC)], albeit a not perfectly defined cell, doesnt express all of the
features of the mature phenotype. Therefore, its a bit of an ill-defined
Nevertheless, that EPC has been shown in multiple preclinical
models to restore microcirculation and, along with it, to rescue hibernating
myocardium. So thats where our efforts have begun.
The group from Frankfurt, Germany, has developed a method of
enriching for endothelial progenitor cells by a culture method. That was the
basis for the REPAIR-MI study, which was recently published in The New
England Journal of Medicine. It was a very important proof-of-concept study
suggesting that in patients who were completely revascularized after myocardial
infarction, you could further improve left ventricular recovery by infusing
these autologous cells. From a standpoint of microvascular protection or
repair, the endothelial progenitor cell is a reasonable place to start, both as
a potential therapeutic and then later on as a possible platform for other
types of repair therapies.
SIMARI: When you think of even short-term culture, how do
you think that that would be applied to large scale trials or even clinical
practice? Will that be a severe limitation, a moderate limitation or not a
limitation if this proves to be efficacious in its wide-scale use?
LOSORDO: As things stand right now in the United States, we
dont have the capacity to do large-scale culturing like the Frankfurt
investigators did to develop that progenitor cell population. Thats why
we chose the CD34 surface marker as a marker of a population of cells
thats enriched for EPCs, because there was already a commercially
available device to select those cells. And so thats your manufacturing
facility, self-contained, so that any hospital can essentially execute this
type of therapy on site as opposed to building factories from these cells.
PATEL: With your trial, youre actually doing both.
You are culturing, but youre using the patient as his or her own
bioreactor using GCSF (granulocyte colony-stimulating factor) to get four days
of extra mobilization of the cells, since your cell can be obtained both from
blood or bone marrow. Its readily available. But in your early research,
Id say mainly its to get that required number of cells from the
blood, you just used the patient to get some of them.
LOSORDO: Thats right. The cells are mobilized.
Theyre not actually cultured so theyre extracted through standard
leuko-apheresis and then purified and readministered, what the FDA refers to as
a minimally manipulated cell and, therefore, it doesnt need to pass the
GMP (good manufacturing practices)-type facility requirements that a cultured
VAUGHAN: There are companies that exist now and that
already have closed system platforms that allow for relatively short-term
cultured expansion of specific subpopulations of cells. You can have bone
marrow taken from the patient transferred to the facility, expanded for a
couple of weeks and returned, its all in a sterile environment.
Thats possible and thats being used now for nonhealing fractures
and things like that.
PEPINE: In the cardiac field the skeletal myoblast work has all
been done that way.
ANNEX: Its an important point to remember that we
need to be doing a better job at characterizing these cells as we go forward. I
think its worth restating that just because a cell has a CD34 marker, it
will have a whole number of other markers. Therefore, one of the things that I
think is going to be very critical for this field as it moves forward is to
recognize that there is a big difference between cells and drugs.
Theres going to be variability from one site to another. The
commercially available devices that are attempting to improve on that are a
major step forward, but studies should really look to be certain at the end of
the day what the degree of heterogeneity is from one patient to another, one
site to another and how those may ultimately impact on therapy. At least in the
angiogenesis and gene therapy area, you knew that two places around the country
were giving the same milligram amount of DNA in whatever form and the same
amount of recombinant protein. With the cells those are going to be
SIMARI: The field of cell therapy for cardiovascular
disease is developing as the field of cell delivery for other diseases may be
more advanced. I think we need to learn from these other experiences and as
Doug pointed out, were using CD34 cells because theyre available
and were developed for stem cell delivery. One of the lessons from stem cell
therapy that I find intriguing, is that you can give bone marrow systemically
and it knows where to go.
The second is that dose response is very different. Cells are a
heterogeneous mix when they do a bone marrow transplant. Dose responses differ
from traditional drug studies. Maybe were going to have to develop these
with some unknowns based upon uncertainties of what cell delivery is. They are
not drugs. Theyre regulated like drugs, but theyre not drugs.
Part two of this round table will be published in Today
in Cardiologys March issue.