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Stem Cells in the Cath Lab

Evaluating Intracoronary Injection of Cardiac Stem Cells for Recent Myocardial Infarction: The CADUCEUS Trial

October 2009

Cath Lab Digest and Clinical Editor Dr. Morton Kern talk with CADUCEUS Principal Investigator Raj Makkar, MD, Director, Interventional Cardiology and Cardiac Catheterization Laboratory, Cedars-Sinai Medical Center, Los Angeles, California Can you describe the CADUCEUS trial? The CADUCEUS acronym stands for Cardiosphere-Derived Autologous Stem Cells to Reverse Ventricular Dysfunction. This trial is a National Institutes of Health (NIH) and Cedars-Sinai sponsored Phase I, randomized, dose escalation study of the intracoronary administration of autologous cardiosphere-derived stem cells in patients with a recent myocardial infarction. The trial’s primary endpoint is safety of the administration of autologous cardiosphere-derived stem cells, but the secondary objective is also to evaluate the efficacy of this procedure. CADUCEUS will enroll between 24-30 patients with a prior myocardial infarction within four weeks. Once a patient is enrolled, an endomyocardial biopsy is performed, which is the source of the stem cells administered upon a repeat procedure. The endomyocardial biopsy is processed at an outside laboratory. It takes about 4 to 6 weeks to harvest an adequate number of cardiosphere-derived stem cells, which are then reinfused in the infarct-related artery. This is a separate procedure in the cath lab, with the intention of obtaining myocardial repair. The trial, as a dose escalation study, will look at two different cell doses. The low dose is 12.5 million cells and the high dose is 25 million cells. The first 6 patients will be randomized in a 2:1 fashion to low-dose cardiosphere-derived stem cells versus control (4 patients receive cells, 2 are in the control group) and then the subsequent 18 patients will be randomized in a 2:1 fashion to high-dose cardiosphere-derived stem cells versus control (12 patients receive cells, 6 patients are in the control group). Both doses have been tested in preclinical studies (in a pig infarction model) and have been found to be quite safe. How unique is the CADUCEUS trial? There are a number of different cell types currently being studied, including bone marrow-derived mononuclear cells, mesenchymal stem cells, and endothelial progenitor cells. Myoblast injection studies are also ongoing. The CADUCEUS trial is unique because it marks the first time autologous cardiac stem cells have been used in patients. There are many advantages to using autologous cardiosphere-derived cells: 1. This cell mixture includes c-kit positive cells (a type of stem cell), but also other nourishing cells which may be vital in terms of obtaining myocardial repair. 2. These cells are predestined to be cardiomyocytes and blood vessels, so it makes more sense to use them. 3. Autologous cardiac stem cells (i.e. coming from the patient’s own heart) are not limited by the immunogenic response. 4. Ethically, they are much more palatable to people who are against embryonic stem cell research. 5. They are harvested very easily through a percutaneous approach. You mentioned patients must have a prior acute MI within the past four weeks. Yes. The efficacy of this procedure was first demonstrated in acute MI models. While we are starting off in patients with acute MI, ultimately our goal is to expand to patients that have a history of remote MI and ischemic cardiomyopathy. I do think chronic MI is where we will see the greatest impact for this type of therapy, because there are hundreds of thousands of patients in the United States alone with remote MIs and chronic ischemic cardiomyopathy. We will be working with the FDA in the coming months in the hopes of expanding the protocol to these patients. Is there any significant risk to these procedures? I think that is an excellent question. First of all, it’s been done hundreds of times in a preclinical model, in pigs, and was found to be safe. For the biopsy, the goal is to take small pieces of tissue from the right ventricle (RV), accessed from the jugular vein using a bioptome. We are aware of the possible issues and therefore we properly screen our patients with a baseline cardiac MRI to ensure there is enough viable tissue on the RV side and no transmural MI of the septum. The biopsy itself is a procedure that can be done within 20 minutes using echo guidance. It requires no contrast and very little radiation. For centers such as ours where we have a fair number of cardiac transplantations and a high heart transplant volume, it’s a very routine procedure. Patients can leave the hospital typically within 2 hours, but we do monitor these patients for up to 6 hours after we do an endomyocardial biopsy. From that point, what happens to the cells that are harvested? The biopsy specimens are processed in a cell manufacturing laboratory which was established with the leadership of Dr. Eduardo Marbán, director of the Cedars-Sinai Specialized Center for Cell-based Therapy and the Cedars-Sinai Heart Institute. The biopsy tissue is cultured and gives rise to globular structures called cardiospheres. They are not beating in humans, but in mice, they actually have spontaneous beating capacity. The cardiospheres are further cultured and go through a number of passages to give rise to CDCs, or cardiosphere-derived cells. In a matter of 4 to 6 weeks, we can typically arrive at anywhere from 12 to 25 million cells, which is the cell dosage required as the test dose in the clinical trial. Cardiospheres themselves have been found to be therapeutically effective in preclinical studies done by Dr. Marbán. However, the advantage of using CDCs is their small size, allowing them to be administered very safely in an intracoronary fashion compared to cardiospheres, which are much larger and would therefore flood the intracoronary circulation if given via an intracoronary route. Does it matter where in the right ventricle the cells are harvested? Our goal is to take RV biopsies from areas that have normal muscle, which is something we try to identify with the initial cardiac MRI. Once cultured, how are the cardiosphere-derived stem cells injected? The intracoronary injection protocol is very similar to the REPAIR-AMI (Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction) trial or the REVITALIZE (Randomized Evaluation of Intracoronary Transplantation of Bone Marrow Stem Cells in Myocardial Infarction) trial. In the cath lab, an over-the-wire balloon is advanced in the infarct-related coronary artery which has been stented. For example, if there is a stent in the proximal left anterior descending artery (LAD), we will wire the LAD, advance an over-the-wire balloon, position it within the stent, and inflate the balloon so the blood flow in the artery is temporarily occluded. The guidewire is withdrawn and the cells are administered through the lumen of the over-the-wire balloon. The resulting stasis allows some of the cells to house into the myocardial tissue. The protocol is to have the balloon up for 3 minutes and down for 3 minutes, for a total of 3 times. The entire process of injecting the cells takes about 20 minutes. We are currently doing preclinical studies with direct injection of cells using the Noga Cardiac Navigation System (Biosense Webster, a Johnson & Johnson company). The Noga system uses electromechanical mapping to identify the area of infarct. It has a specialized catheter injection system enabling direct injection of cells into areas surrounding infarcted tissue. There is a mapping catheter that measures the mobility and voltage of the tissue. The injection catheter also has navigation incorporated into it, allowing the precise injection of cells at the desired location. Our goal is to eventually use the Noga system to inject the cells through an endocardial approach. Does the region receiving the cells have to be viable? We are injecting the cells in the infarct-related arteries, so it is in an area that has been infarcted, has a sub-endocardial MI or some regional wall motion abnormality. Is it possible to deliver cells to an infarcted but a collaterialized bed? We have no data about the administration of these cells through collaterals. I would think that it should not be a problem. It will hopefully be studied in future protocols. What’s the pharmacologic regimen in the post-implant period? Patients continue aspirin and clopidogrel according to what they would normally do post-PCI. They are treated with the usual medications, ACE inhibitors and beta blockers, as indicated. There is no significant change in the way these patients are treated. We will, however, make sure that these patients are optimally managed medically in order to demonstrate that any resulting benefit is actually over and above proven clinical treatment. How are you assessing patient response? We are doing a baseline cardiac MRI and looking at the infarct sites, left ventricular dimensions and ejection fraction, and then repeating the cardiac MRI at 6 months to assess these parameters again. While the primary endpoint is the safety of administration of these cells, we are also collecting information pertaining to efficacy. How long are you following patients? We are in the early aspects of the study, but we will be following patients up to a year. Is there any known systemic effect to having received these cells? In preclinical studies, there are no known systemic effects and no known tumor formations. What centers are participating? At this point, Cedars-Sinai and Johns Hopkins are the only two centers participating in this protocol. As we move forward and into larger studies, it is conceivable that we will have more sites. The first objective is to conclude the study and demonstrate its safety to the FDA. Dr. Makkar can be contacted at Raj.Makkar@cshs.org

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