Early Preliminary Data From Ongoing Bone Marrow Stem Cell Studies: TOPCARE-DCM, TECAM, and Phas
Early Preliminary Data From Ongoing Bone Marrow Stem Cell Studies: TOPCARE-DCM, TECAM, and Phase 1 Mesenchymal Cell Study
At the Second International Conference on Cell Therapy for Cardiovascular Diseases, held January 19-21, 2006, in New York, NY, interim data from 3 ongoing trials of bone marrow-derived cells (BMCs) -- with intracoronary infusion, autologous derivation, or as mesenchymal cells -- were presented.
TOPCARE-DCM
Following their studies of Transplantation of Progenitor Cells And Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) and Coronary Heart Disease (TOPCARE-CHD), the same group of researchers at JW Goethe University in Frankfurt, Germany, is conducting TOPCARE-DCM, a pilot study to determine whether intracoronary infusion of bone marrow-derived stem cells into the left anterior descending artery can improve left ventricular (LV) function in 20 patients with dilated cardiomyopathy.
To date,8 patients have completed 12 months of follow-up, and since the initial results were announced in November 2005, all patients have undergone 3-month coronary angiography. Andreas M. Zeiher, MD, Professor of Medicine and Director of Medical Clinic IV/Cardiology at University Hospital Frankfurt, reported that to date a "modest, but significant" 3% improvement has been seen in LV ejection fraction (from mean 29% to 32%, P = .001), with significant reductions in global hypokinesia and global contractility. No effect on LV end-diastolic volume has been recorded, although there is a trend toward a decrease in LV end-systolic volume. In addition, there has been improvement in contractility of the area targeted by the cell infusion in some patients. A significant decrease of almost 50% in serum N-terminal atrial natriuretic peptide (NT-proANP) was seen at 12 months, suggesting an overall improvement in cardiac function.
The technique of intracoronary cell infusion (via balloon occlusion for 3 x 3 min), has been well tolerated, with no increases in troponin T levels (indicating no myocardial damage) and no severe adverse events (death, stroke, myocardial infarction [MI], de novo stenosis) reported over the first 12 months. One patient developed syncope at 3 months and 1 developed de novo ventricular tachycardia between 3 and 12 months, however. Prof. Zeiher and his colleagues plan to start a randomized trial using this technique in patients with nonischemic heart failure.
TECAM
The TECAM group (Terapia Celular Aplicada al Miocardio) of researchers, based in Valladolid, Spain, is performing a series of preclinical and clinical studies aimed at assessing different aspects of stem cell therapy on the treatment of various cardiovascular diseases. Francisco Fernández-Avilés, MD, PhD, Director of the Instituto de Ciencias del Corazón at the Hospital Clinico-Universitario, reported preliminary results of an ongoing nonrandomized study of autologous mononuclear BMCs in patients with extensive acute ST-segment elevation MI (STEMI) who already had successful revascularization.
As of November 2005, 71 patients had received an average of 90 x 10 BMCs per patient 10 days after MI. No adverse events were seen with regard to microvascular function or additional myocardial injury. Forty-eight patients completed 6 or 9 months of follow-up according to whether they had received a bare-metal or sirolimus-eluting stent, respectively. After a mean follow-up 18 months, 1 patient had an MI/treatment related cardiac event, 1 patient had a stroke/transient ischemic attack at 1 month, and 4 (5.6%) patients had ventricular tachycardias 1, 2, and 3 days and 1 month after cell infusion, respectively. Quantitative coronary angiography showed a low rate of in-stent restenosis (17.4%);restenosis was more frequent in the patients who had a bare stent compared with the sirolimus-eluting stent (20% vs 11%). Benefit in terms of remodeling was "clear, but modest," Prof. Fernández-Avilés told attendees.
At odds with many other researchers, Prof. Fernández-Avilés believes that, despite some obvious safety issues, large-scale trials powered to detect mortality benefit should be carried out with BMC infusions. He also believes that more animal studies are needed to identify the subset of patients most likely to benefit from this therapy.
Phase 1 Study With Bone Marrow-Derived Mesenchymal Cells
A new approach being investigated in stem cell therapy is the use of bone marrow-derived mesenchymal cells. These cells have the capacity to differentiate into specialized cells including myocardial and endothelial cells. A phase 1 safety and dose-finding study with these cells is ongoing in acute MI patients. The randomized (2:1), double-blind, placebo-controlled study is being carried out at 17 US sites. Patients entered are aged 21-85 years, presenting within 10 days of AMI (not necessarily STEMI), with creatine kinase within 2 x the upper limit of normal. All have a patent infarct-related artery and an LV ejection fraction of 30% to 60%. Three active treatment cohorts, 0.5, 1.6, and 5 x 10 mesenchymal cells per kg, will be followed for 6 months, with a fourth cohort receiving the highest tolerated of these doses. All patients will be followed for an additional 18 months for safety, evaluated by echocardiography and magnetic resonance imaging and whole-body computed axial tomography scans to eliminate any increased risk of tumor formation.
Enrollment began in March 2005 and is expected to be complete by 2006. Lead study investigator Joshua M. Hare, MD, Professor of Medicine at Johns Hopkins University (Baltimore, Maryland), explained that the advantages of using mesenchymal stem cells are that they are easy to obtain and expand in vitro and they can be used for allogeneic administration, avoiding the need for preparing autologous cells from the recipient. Of importance, the cells are delivered directly to necrotic myocardium rather than through intracoronary injection. The safety and potential for cardiac repair of these cells were previously demonstrated by Dr. Hare and co-investigators in a pig model of MI. Investigation in patients with heart failure is planned.
These studies are supported by Osiris Therapeutics (Baltimore, Maryland), which is developing the first-in-field mesenchymal stem cell product, Provacel, in cooperation with Boston Scientific Corporation (Natick, Massachusetts).
References
At the Second International Conference on Cell Therapy for Cardiovascular Diseases, held January 19-21, 2006, in New York, NY, interim data from 3 ongoing trials of bone marrow-derived cells (BMCs) -- with intracoronary infusion, autologous derivation, or as mesenchymal cells -- were presented.
TOPCARE-DCM
Following their studies of Transplantation of Progenitor Cells And Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) and Coronary Heart Disease (TOPCARE-CHD), the same group of researchers at JW Goethe University in Frankfurt, Germany, is conducting TOPCARE-DCM, a pilot study to determine whether intracoronary infusion of bone marrow-derived stem cells into the left anterior descending artery can improve left ventricular (LV) function in 20 patients with dilated cardiomyopathy.
To date,8 patients have completed 12 months of follow-up, and since the initial results were announced in November 2005, all patients have undergone 3-month coronary angiography. Andreas M. Zeiher, MD, Professor of Medicine and Director of Medical Clinic IV/Cardiology at University Hospital Frankfurt, reported that to date a "modest, but significant" 3% improvement has been seen in LV ejection fraction (from mean 29% to 32%, P = .001), with significant reductions in global hypokinesia and global contractility. No effect on LV end-diastolic volume has been recorded, although there is a trend toward a decrease in LV end-systolic volume. In addition, there has been improvement in contractility of the area targeted by the cell infusion in some patients. A significant decrease of almost 50% in serum N-terminal atrial natriuretic peptide (NT-proANP) was seen at 12 months, suggesting an overall improvement in cardiac function.
The technique of intracoronary cell infusion (via balloon occlusion for 3 x 3 min), has been well tolerated, with no increases in troponin T levels (indicating no myocardial damage) and no severe adverse events (death, stroke, myocardial infarction [MI], de novo stenosis) reported over the first 12 months. One patient developed syncope at 3 months and 1 developed de novo ventricular tachycardia between 3 and 12 months, however. Prof. Zeiher and his colleagues plan to start a randomized trial using this technique in patients with nonischemic heart failure.
TECAM
The TECAM group (Terapia Celular Aplicada al Miocardio) of researchers, based in Valladolid, Spain, is performing a series of preclinical and clinical studies aimed at assessing different aspects of stem cell therapy on the treatment of various cardiovascular diseases. Francisco Fernández-Avilés, MD, PhD, Director of the Instituto de Ciencias del Corazón at the Hospital Clinico-Universitario, reported preliminary results of an ongoing nonrandomized study of autologous mononuclear BMCs in patients with extensive acute ST-segment elevation MI (STEMI) who already had successful revascularization.
As of November 2005, 71 patients had received an average of 90 x 10 BMCs per patient 10 days after MI. No adverse events were seen with regard to microvascular function or additional myocardial injury. Forty-eight patients completed 6 or 9 months of follow-up according to whether they had received a bare-metal or sirolimus-eluting stent, respectively. After a mean follow-up 18 months, 1 patient had an MI/treatment related cardiac event, 1 patient had a stroke/transient ischemic attack at 1 month, and 4 (5.6%) patients had ventricular tachycardias 1, 2, and 3 days and 1 month after cell infusion, respectively. Quantitative coronary angiography showed a low rate of in-stent restenosis (17.4%);restenosis was more frequent in the patients who had a bare stent compared with the sirolimus-eluting stent (20% vs 11%). Benefit in terms of remodeling was "clear, but modest," Prof. Fernández-Avilés told attendees.
At odds with many other researchers, Prof. Fernández-Avilés believes that, despite some obvious safety issues, large-scale trials powered to detect mortality benefit should be carried out with BMC infusions. He also believes that more animal studies are needed to identify the subset of patients most likely to benefit from this therapy.
Phase 1 Study With Bone Marrow-Derived Mesenchymal Cells
A new approach being investigated in stem cell therapy is the use of bone marrow-derived mesenchymal cells. These cells have the capacity to differentiate into specialized cells including myocardial and endothelial cells. A phase 1 safety and dose-finding study with these cells is ongoing in acute MI patients. The randomized (2:1), double-blind, placebo-controlled study is being carried out at 17 US sites. Patients entered are aged 21-85 years, presenting within 10 days of AMI (not necessarily STEMI), with creatine kinase within 2 x the upper limit of normal. All have a patent infarct-related artery and an LV ejection fraction of 30% to 60%. Three active treatment cohorts, 0.5, 1.6, and 5 x 10 mesenchymal cells per kg, will be followed for 6 months, with a fourth cohort receiving the highest tolerated of these doses. All patients will be followed for an additional 18 months for safety, evaluated by echocardiography and magnetic resonance imaging and whole-body computed axial tomography scans to eliminate any increased risk of tumor formation.
Enrollment began in March 2005 and is expected to be complete by 2006. Lead study investigator Joshua M. Hare, MD, Professor of Medicine at Johns Hopkins University (Baltimore, Maryland), explained that the advantages of using mesenchymal stem cells are that they are easy to obtain and expand in vitro and they can be used for allogeneic administration, avoiding the need for preparing autologous cells from the recipient. Of importance, the cells are delivered directly to necrotic myocardium rather than through intracoronary injection. The safety and potential for cardiac repair of these cells were previously demonstrated by Dr. Hare and co-investigators in a pig model of MI. Investigation in patients with heart failure is planned.
These studies are supported by Osiris Therapeutics (Baltimore, Maryland), which is developing the first-in-field mesenchymal stem cell product, Provacel, in cooperation with Boston Scientific Corporation (Natick, Massachusetts).
References
Schachinger V, Assmus B, Britten MB, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial. J Am Coll Cardiol. 2004;44:1690-1699.
Assmus B, Honold J, Schächinger V, et al. Transcoronary Transplantation of Progenitor Cells in Patients with Persistent Left Ventricular Dysfunction after Myocardial Infarction: A Randomized Controlled Trial (TOPCARE-CHD). Circulation. 2005;112(Suppl II):II-632. Abstract 2984.
Zeiher A. Bone marrow mononuclear cells for nonischemic myocardial disease. Program and abstracts from the Second International Conference on Cell Therapy for Cardiovascular Diseases; January 19-21, 2006; New York, NY.
Fischer-Rasokat U, Assmus B, Honold J, et al. Selective Intracoronary Infusion Of Bone Marrow-derived Progenitor Cells In Patients With Non-ischemic Dilated Cardiomyopathy: Initial Results Of The TOPCARE-DCM Trial. Circulation. 2005;112(Suppl II):II-580. Abstract 2751.
Fernández-Avilés F. The Valladolid intracoronary bone marrow experience. Program and abstracts from the Second International Conference on Cell Therapy for Cardiovascular Diseases; January 19-21, 2006; New York, NY.
Hare J. Mesenchymal cells in acute MI: promise and potential. Program and abstracts from the Second International Conference on Cell Therapy for Cardiovascular Diseases; January 19-21, 2006; New York, NY.
Amado LC, Saliaris AP, Schuleri KH, et al. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc Natl Acad Sci U S A. 2005;102:11474-11479.
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