Cardiovascular cell therapy research: Keep preclinical work going and move into the clinic

United States lags behind Europe and Latin America in cell therapy.

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.

Moderator
Carl J. Pepine, MD Eminent Scholar, Professor and Chief, Division of Cardiovascular Medicine, University of Florida, Gainesville, and Chief Medical Editor of Today in Cardiology.	Brian H. Annex, MD Director of Vascular Medicine and Vice Chief, Division of Cardiovascular Medicine, Duke University
Robert D. Simari, MD Professor of Medicine and Chair of Cardiovascular Research, Mayo Clinic, Minnesota	Douglas Losordo, MD Professor of Medicine, Director of the Feinberg Cardiovascular Research Institute and Program in Regenerative Medicine, Northwestern University Medical School
Douglas Vaughan, MD Chief of Cardiovascular Medicine, Vanderbilt University	Amit N. Patel, MD Director of Cardiac Cell Therapies at McGowan Institute for Regenerative Medicine, University of Pittsburgh

CARL J. PEPINE, MD: We’re 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 to patients?

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 what’s 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 we’ve learned from the lab and moving it into patients, but also understanding what we’re 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 can’t disagree with what’s 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 it’s not going to happen unless there’s a kind of cross-talk.

DOUGLAS LOSORDO, MD: It’s a time of great promise and that adds enormous burden of responsibility when there’s this much expectation, especially in the community. I think it’s our job, to a certain extent, to control the conversation and make sure that people’s 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 it’s interpreted very conservatively and that there’s dialogue.

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 we’re attempting to do.

PEPINE: Amit, you’re 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 advantage.

It’s not just as we’re 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 they’ve 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. They’ll bring in printouts of vast amounts of information and that’s all it is. It’s information and it’s our job to really decipher what they have and tell them the reality. They may not be false promises, but they’re unproven promises that based on their disease when we evaluate them, could often benefit from standard medical care. They’re just under-managed in the current environment that they’re 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 that’s still unproven.

PEPINE: That’s 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, what’s 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 that’s 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 that’s 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? I’m 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 we’ll be.

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: There’s a big difference, however, in terms of what the strategy is when you talk about the peripheral vasculature and the heart. In the heart we’re talking about generally trying to improve contractile function somehow. In the peripheral vasculature, we’re 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, they’re not completely overlapping in terms of what you’re 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, that’s the biggest issue. All these routes that everyone takes, whether it’s intracoronary, coronary sinus, endocardiac, epicardial, the retention of cells is so low that it’s very difficult to say realistically that when you translate from our preclinical studies to humans that sometimes you’re looking in the neighborhood of only 3% to 10% [retention] of the cells. It’s 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 don’t 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: That’s 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 that’s 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 type?

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, doesn’t express all of the features of the mature phenotype. Therefore, it’s a bit of an ill-defined entity.

Nevertheless, that EPC has been shown in multiple preclinical models to restore microcirculation and, along with it, to rescue hibernating myocardium. So that’s 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.

PEPINE: Enhanced?

LOSORDO: Correct.

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 don’t have the capacity to do large-scale culturing like the Frankfurt investigators did to develop that progenitor cell population. That’s why we chose the CD34 surface marker as a marker of a population of cells that’s enriched for EPCs, because there was already a commercially available device to select those cells. And so that’s 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, you’re actually doing both. You are culturing, but you’re 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. It’s readily available. But in your early research, I’d say mainly it’s to get that required number of cells from the blood, you just used the patient to get some of them.

LOSORDO: That’s right. The cells are mobilized. They’re not actually cultured so they’re extracted through standard leuko-apheresis and then purified and readministered, what the FDA refers to as a minimally manipulated cell and, therefore, it doesn’t need to pass the GMP (good manufacturing practices)-type facility requirements that a cultured cell would.

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, it’s all in a sterile environment. That’s possible and that’s 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: It’s an important point to remember that we need to be doing a better job at characterizing these cells as we go forward. I think it’s 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.

There’s 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 different.

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, we’re using CD34 cells because they’re 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 we’re going to have to develop these with some unknowns based upon uncertainties of what cell delivery is. They are not drugs. They’re regulated like drugs, but they’re not drugs.

Part two of this round table will be published in Today in Cardiology’s March issue.