March 01, 2007
14 min read

Part II: Best route for delivering cell therapy needs further study

The intracoronary route may be easy, but is probably not feasible or effective in all situations.

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Cardiology Today 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 two of the round table is presented here. Part one was published in the February issue of Cardiology Today.


Carl J. Pepine, MDCarl J. Pepine, MD
Eminent Scholar, Professor and Chief, Division of Cardiovascular Medicine, University of Florida, Gainesville, and Chief Medical Editor of Cardiology Today.

Brian H. Annex, MDBrian H. Annex, MD
Director of Vascular Medicine and Vice Chief, Division of Cardiovascular Medicine,
Duke University

Robert D. Simari, MDRobert D. Simari, MD
Professor of Medicine and Chair of Cardiovascular Research,
Mayo Clinic, Minnesota

Douglas Losordo, MDDouglas Losordo, MD
Professor of Medicine, Director of the Feinberg Cardiovascular Research Institute and Program in Regenerative Medicine,
Northwestern University Medical School

Douglas Vaughan, MDDouglas Vaughan, MD
Chief of Cardiovascular Medicine,
Vanderbilt University

Amit N. Patel, MDAmit N. Patel, MD
Director of Cardiac Cell Therapies at McGowan Institute for Regenerative Medicine, University of Pittsburgh

CARL J. PEPINE, MD: In part one of this round table, we talked about the future of stem cell therapy research and whether is it time to move into the clinical arena with research. Let’s talk this time about how stem cells should be delivered.

BRIAN H. ANNEX, MD: Intramyocardial delivery remains a problem and concern. There are catheters designed for intramyocardial delivery. Some are a little bit better, some are a little bit worse. To some degree, there’s not been the impetus for device companies to develop catheters for intramyocardial delivery if there are no cells to deliver. As the field expands and as there’s a greater awareness of the potential for this field to move forward, hopefully that will be overcome.

Intracoronary delivery can be feasible for some cell types, probably not all and I think, again, this will be a very important area. This is the one area that I think we probably under study as we go from preclinical to clinical. It’s a lot easier to regulate delivery in a preclinical setting than it is in a clinical setting. As we move into patients and explain these risks to the patients, that’s something we’re going to have to consider. Obviously, surgical delivery is not a problem, but this restricts your patient population somewhat significantly.

PEPINE: It would be easier if we could give the cells by an intracoronary route. I think we’d all agree that’s the simplest, most direct route to myocardium, and we’ve had 40 years of experience with intracoronary injections.

DOUGLAS VAUGHAN, MD: We’re so early in this field it’s hard to imagine we’re even close to doing what we need to do to optimize the number of cells that take up residence where we want them to live and whether or not that requires retrograde infusions or long dwell times or cells delivered under pressure or through a loop.

PEPINE: I agree. But if we could deliver the cells through intracoronary injection, then, why not just give it systemically? They know where to go. What about other stem cells? Do we want to go into nonautologous cells?

ROBERT D. SIMARI, MD: There is some intriguing evidence on mesenchymal stem cells that should be pursued in an allogeneic fashion. The resident progenitor cell should be pursued in an autologous fashion. We’re just scratching the surface on the cells that are possible to be used, but I see those as two cell types with potential.

PEPINE: What’s happened to cardiospheres from the biopsy? Is that possibility moving along?

VAUGHAN: I think it is. They have a company and they’re doing something at Hopkins, but I don’t know how far along they are, if they’re delivering in humans. The data that they have are pretty impressive that they can culture out some cells that will proliferate and will exhibit contractile properties and things like that over time.

PEPINE: Has any other group done this?

DOUGLAS LOSORDO, MD: I think Roberto Bollie and Pierore Anversa have a cardiac progenitor cell c-Kit positive cell and that they will start a phase-1 study. They’re in the last phase of an IND application so they’re planning to start the study soon. It’s an autologous cell derived from a biopsy specimen grown in culture from a patient and then selected with a c-Kit antibody, and then administered to the patient by, I believe, an intramyocardial injection for patients with heart failure.

PEPINE: What about these cells as a platform to deliver other therapy? What do you think about this possibility?

SIMARI: From a regulatory perspective, to utilize gene delivery would raise the bar and make it much more difficult to move into the clinic at an early phase. Doing so without understanding what the cell alone does would be a mistake. But clearly, genetic modification of cells has great potential.

Probably, as Amit (Patel) mentioned, with delivery issues, even in the worst situation, delivery of a cell may be better than we could ever do with gene delivery under the best circumstances. So, even if it’s a bad cell, it might be a fine gene delivery tool, especially if you’re generating a replicating vector system or something like that. I think that holds great potential.

VAUGHAN: Creating a super cell is really an exciting idea, but, as Bob (Simari) said, I think the regulatory hurdles that would preclude that at this point in time are just overwhelming. So that’s way off in the distance. Preclinical work can of course be done, but bringing that into clinical, I don’t see it happening.

LOSORDO: I would look at it maybe from a slightly different perspective. One of the things that has emerged from preclinical and even to a certain extent from the early phase clinical studies is the heterogeneity of cells that we collect from patients. We have shown that the cells of healthy volunteers are much better at repairing ischemic tissue than the cells from the patients who we want to treat.

As we begin to learn more and more about what it is that creates a functional vs. a nonfunctional stem cell phenotype, we will have opportunities to modify these cells to improve their functional capacity. Yes, there is a lot of preclinical science that still needs to be done.

From the standpoint of gene modification of these cells, I think that does add a little bit of a regulatory burden. On the other hand, from the perspective of a gene therapist, the idea that you can execute your gene therapy outside of the patient and then really just administer your cell-targeted vector to the targeted organ and not have to worry so much about systemic effects, maybe there’s a safety advantage that’s built into that strategy as well.

SIMARI: There was a clinical study approved for delivery of a smooth muscle progenitor and an endothelial progenitor, both of which I think were transduced. Isn’t that right?

ANNEX: I believe that’s right. The science should really drive this. We should not be deterred by regulatory hurdles in and of themselves. If the science and the questions are compelling enough, then we should constitutionally and as an investigative community take the steps to get those through. I think that’s very, very critical. I think the opportunity to level the playing field, to alter the cells, is really too appealing. The ability to understand better aspects of gene transfer, that opportunity is really there.

I also want to comment that the delivery of a gene or gene product to the cell outside to the body really can be used in two different ways. One is it can alter the potential viability or survival of the cell, not only in addition to being simply a factory for producing the transgene product. So, actually it has multiple potential beneficial effects.

AMIT N. PATEL, MD: By adding gene products, you could most likely, in the preclinical model, see an increase only of those cells to specifically injured areas. You might increase retention and you may potentially improve targeting of cells to injured areas and enable tracking at the same time. If you could tell the cells where to go, then delivery becomes a lot easier.

PEPINE: So far, our focus has been ischemic heart disease and repairing myocardial or vascular dysfunction. What about other cardiovascular applications? Let’s say we could design a cell to repopulate your grafts that would be advantageous. Or maybe a cell to line valves that is antithrombogenic, has tremendous durability, etc. What do you think about other applications?

PATEL: Bioengineering, it’s incredible what the potential is. There are preclinical data for valves and vascular conduits where using either autologous cells or these mesenchymal cells lining bioengineered valves or dissolvable conduits with either polyurethane or even autologous oncology vasomaterials offers great potential for the future. It’s just another leap in the science. Now you’re not only looking at the cells, but also the grafts that you’re using to create them. But there is already clinical work in vascular grafts being done in Japan.

SIMARI: But we’ve been interested mostly in the use of autologous cells in vascular protection and the difficulty with the graft is a large graft doesn’t re-endothelialize so you don’t need to re-endothelialize that. What you need to do is keep a small graft open. Obviously that would be a holy grail, if one could develop a non-thrombotic graft that small in diameter. If you think broadly about vascular structure, could one use cell delivery to help aneurysms heal or to prevent aneurysm dilatation? The challenges there are much different than working in a small 3 mm graft, but it’s a very complex inflammatory and immunologically active lesion. If one could use cells to modify that, now there’s a strategy that might have some clinical impact. The other thing that we’ve been working on is how to put — as others have done — endothelial cells and progenitors on stents to try to re-endothelialize and reduce thrombotic complications of stents.

PEPINE: Has anybody tried to reengineer vascular smooth muscle cells so that the phenotype is converted to a phenotype that has more potential for proliferation and migration, to mimic the natural response for repair that is dysfunctional in these patients?

ANNEX: That was the E2F decoys where there was an attempt to modify the vascular smooth muscle in a vein prior to grafting. While it was very encouraging in the early phases, it was not effective in a larger scale trial.

It is a very important topic. Again, you have other ways of obviously delivering the transgene products. The liver, for example, may be one of the best biogenerators we have if we want secretory proteins, assuming they’re not going to be modified by the lung as you pass through. The heart would actually be another one; again, if you had to get on the arterial side. There you have to consider clearly the long-term viability of the cell and the long-term viability of the vector you’re using to express the product.

LOSORDO: Two new therapeutic targets to consider would include stroke and diabetic skin ulcers. As efforts to revascularize target vessels in stroke patients increase, the next step will be to improve long-term outcomes using novel therapies. The evolution of this paradigm will be accelerated by lessons learned in the development of therapies for post-MI patients. With the growing diabetic population and the increasing burden of vascular disease, the diabetic skin ulcer is another potential target. Cellular therapy of wounds has been shown in preclinical models to be effective. There are some early clinical trials underway which could bring this dreaded condition a bit more under control. The wound, of course, of the diabetic is the No. 1 reason for hospital admission and it would be nice to see us make some progress in managing these patients with a novel therapeutic.

PEPINE: Nephrologists boast that the only organ that’s not been successfully reconstituted in animal models, cell therapy-wise, is the nephron. Is that true?

PATEL: There are data for ATN, maybe not chronic renal failure, but for ATN that doesn’t recover on its own. The progression of that they’ve shown in the small animal, using a cell-based therapy. That’s been published. [It] can reduce the scarring process. But, out of all the diseases we’ve talked about, that probably has the least amount of even preclinical data right now.

ANNEX: The cell therapy field, as it evolves, will also potentially help us understand other fields, [including] the angiogenesis field, which continues to be at delay trying to get at comparable questions. I don’t think there’s any question that the cellular response is probably very much a part of that.

Similarly, there are other drugs that are attempting to pharmacologically mobilize cells, CXCR4 antagonists for example, which have been studied in other diseases, are actually beginning to come on the horizon as a way to mobilize cells from the bone marrow. As we understand more about the cells and the cell types, this will probably cross-fertilize to other areas.

VAUGHAN: From a cardiovascular perspective though, it’s important to note that most of the work that’s been done in the clinical arena so far has involved patients in the subacute setting post-myocardial infarction, for people with chronic ischemic heart disease. Very little [has been] done with cardiomyopathy yet. There’s very little room there. We don’t know if that’s a population that will benefit. We don’t know what types of cardiomyopathies might be targeted. Are there some that might respond or others that won’t? We don’t know.

PEPINE: How about the electrical area? Pacers? Is there some enthusiasm?

SIMARI: Yes, both to generate impulses and block impulses. Doug Packer’s group at Mayo has been using some for AV block and to block atrial fibrillation. The cell delivery numbers are enormous and the number of injections are currently in the hundreds. It’s hard to imagine human translation without further optimization. The biologic pacemaker has potential interest in asking cells to do something that they should be able to do at some level. I remain enthusiastic that, at some level, cell grafts may be used as back-up pacing.

PEPINE: There’s one area that I didn’t touch and that’s the area of just using growth factors to release more of the patient’s own cells. Where do you think that’s going?

PATEL: The potential is there. We don’t know the quality of those cells. Just by using the markers or knowledge of just markers is still so limited. So, to say for example, the CD34 cell that’s mobilized may have that same CD34, but its biological activity may be very different from an immobilized cell.

LOSORDO: The implication of that approach is a more chronic therapy. In some fashion these cells have been preinstalled by the “manufacturer” for the purpose of tissue repair and there’s plenty of evidence to suggest that, for example, in the setting of myocardial infarction, certain cells are mobilized from the bone marrow for the purpose of dealing with acute ischemic stress.

As a chronic form of therapy in patients who, for one reason or another, are not effectively using their own pool of progenitors, is there a way that we could administer a therapy, maybe an orally administered small molecule drug, to engender more of that repair response on an ongoing basis? I think that’s a very intriguing concept. That’s probably a third or fourth generation strategy, but it’s something that we think about as a long-term goal avoiding some of the issues for cell delivery that we face today.

VAUGHAN: If we really do have resident stem cells in our myocardium that perhaps are dormant or hibernating, if we had the right growth factor or factors to mobilize those and get them to proliferate, that would be terrific. It’s an important area of investigation. [There are] a lot of unknowns still.

ANNEX: I am probably the most enthusiastic about this. I think if we can understand what these cells are and their potential, we can understand pharmacologic and other ways to manipulate them and that would probably be far better than trying to harvest them out of some crude preparation. So, actually, I think that has great potential.

I’d also add that I think a lot of therapies that are coming down the horizon or are showing promises like angiogenic growth factors, particularly in the area of critical limb ischemia where there is positive data from randomized placebo-controlled trials. Understanding the extent to which cells are playing a role in that process is going to be very critical and is actually part of work that we and others are doing right now. If we can pharmacologically manipulate this, that would be far better.

SIMARI: I would say that as long as the pharmaceutical industry is aimed at screening, identifying and developing small molecules and, secondarily peptides, we will always have a push towards developing those for any opportunity, including using it instead of cell therapy. But going a step further, are we sure we don’t already have a drug that works that way?

LOSORDO: Yes, statins.

SIMARI: Statins would be the example. We may already have drugs that work through cell mobilization.

ANNEX: You have statins, you have angiogenesis agents, you have other drugs that may in fact be working through those mechanisms. So, I think, again, as we understand more and more of this — and I hope that as the field evolves — we get away from single markers and evolve to a better understanding of more of a profile of the cells. I am not completely convinced that one marker is going to be definitive in this area.

PEPINE: Let me just ask all of you to give us a take-home message.

SIMARI: To go back to one of your earlier questions in terms of what do we tell our patients who are really interested, beyond state-of-the-art standard care. I would encourage them to get involved in every opportunity for clinical investigation. We should offer them the best clinical investigations there are. I think we should aim to do those studies that allow us to have information to build the next generation of good studies. I have great hope that we will either directly apply the lessons of this field or indirectly apply it through more standard mechanisms, and that these studies will make a big difference in how we care for our patients.

ANNEX: This field has absolutely enormous potential. This has the ability to help us understand the pathophysiology of disease and to develop better strategies in the future. It’s really important that the cardiology community stay united on this and agree that we will tackle whatever problems are there that need to be overcome. It’s a pity to see things held up for – I’m not saying they are but if they are – being held up for regulatory reasons.

I would also encourage that all investigators be cautious about the results. I think we’ve learned what happens if we oversell data. Patients do very well when they enter well-designed clinical trials with very good investigators. We know that and we see that time and time again, even for the sickest of patients. Patients should certainly be encouraged for that and not go after therapies that have no proven value.

VAUGHAN: Elizabeth Nabel and the National Heart, Lung, and Blood Institute deserve recognition and credit for having the vision to create a cell therapy network for studying the use of cells for the treatment of cardiovascular disease. That network is supposed to start next year, pending funding. I think it’s a remarkable statement as to their confidence and optimism about getting the United States into this field.

LOSORDO: We’re at the threshold of something very exciting, that is, the concept that we can really repair tissues that we previously thought were beyond repair. A three-prong attack on this, scientists joining with clinicians and together educating patients and the lay public, can move this field forward in the most effective way.

PATEL: I’m very optimistic about cells, but if it’s used in the right patient population.

With celebrities getting involved, the awareness is increasing, but it’s our job as the clinician or the clinician scientist to focus that enthusiasm into reality to increase patient numbers for our trials. That’s the best way.

Instead of getting these great trials and not finding patients, we could really use media, celebrities, and everyone else who’s involved to at least get them to the places that have all of these great trials. Then the reality sets in that these are very stringently designed trials and maybe less than 5% of the patients who show up, at least to my door, actually qualify for any of these trials. The rest of them have to wait until the next generation of trials, but until then, we still use standard medical care and give them more of a dose of reality.

It’s not that we’re pessimistic, but we’re realists. At the end of the day, all stem cell therapy is, is experimental. So, no matter what entity or wherever you hear it from, that’s all it ever is and for many years to come, still, that’s all it’s going to be.