Philippe Menasché1, Valérie Vanneaux2, Albert Hagège3, Alain Bel4, Bernard Cholley5, Alexandre Parouchev2, Isabelle Cacciapuoti2, Reem Al-Daccak6, Nadine Benhamouda7, Hélène Blons8, Onnik Agbulut9, Lucie Tosca10, Jean-Hugues Trouvin11, Jean-Roch Fabreguettes12, Valérie Bellamy13, Dominique Charron14, Eric Tartour15, Gérard Tachdjian10, Michel Desnos3, Jérôme Larghero16. 1. Department of Cardiovascular Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France; University Paris Descartes, Sorbonne Paris Cité, Paris, France; National Institute of Health and Medical Research (INSERM) U970, Hôpital Européen Georges Pompidou, Paris, France. Electronic address: philippe.menasche@aphp.fr. 2. Cell Therapy Unit, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris, France; INSERM, Clinical Investigation Center in Biotherapies (CBT-501) and U1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France. 3. University Paris Descartes, Sorbonne Paris Cité, Paris, France; National Institute of Health and Medical Research (INSERM) U970, Hôpital Européen Georges Pompidou, Paris, France; Department of Cardiology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France. 4. Department of Cardiovascular Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France. 5. University Paris Descartes, Sorbonne Paris Cité, Paris, France; Department of Anesthesiology and Intensive Care, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France. 6. INSERM U976, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, University Paris Diderot, Sorbonne Paris Cité, Paris, France. 7. Department of Biological Immunology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France. 8. INSERM Mixed Research Units (UMR)-S1147, National Scientific Research Center (CNRS) Non CNRS Structure 5014, Sorbonne Paris Cité, Department of Biochemistry, Pharmacogenetic and Molecular Oncology Unit, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France. 9. Sorbonne Universités, Université Pierre et Marie Curie, University Paris-6, Institut de Biologie Paris-Seine, UMR CNRS 8256, Biological Adaptation and Ageing, Paris, France. 10. Assistance Publique-Hôpitaux de Paris, University Paris Sud, Histology-Embryology-Cytogenetics, Hôpitaux Universitaires Paris Sud, Clamart, France. 11. School of Pharmacy, University Paris Descartes, Paris, France; Central Pharmacy, Pharmaceutical Innovation Department, Assistance Publique-Hôpitaux de Paris, Paris, France. 12. Central Pharmacy, Clinical Trials Department, Assistance Publique-Hôpitaux de Paris, Paris, France. 13. National Institute of Health and Medical Research (INSERM) U970, Hôpital Européen Georges Pompidou, Paris, France. 14. Human Leukocyte Antigen and Médecine, Hôpital Saint-Louis, INSERM U976, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France. 15. University Paris Descartes, Sorbonne Paris Cité, Paris, France; National Institute of Health and Medical Research (INSERM) U970, Hôpital Européen Georges Pompidou, Paris, France; Department of Biological Immunology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France. 16. Cell Therapy Unit, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris, France; INSERM, Clinical Investigation Center in Biotherapies (CBT-501) and U1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France.
Abstract
BACKGROUND: In addition to scalability, human embryonic stem cells (hESCs) have the unique advantage of allowing their directed differentiation toward lineage-specific cells. OBJECTIVES: This study tested the feasibility of leveraging the properties of hESCs to generate clinical-grade cardiovascular progenitor cells and assessed their safety in patients with severe ischemic left ventricular dysfunction. METHODS: Six patients (median age 66.5 years [interquartile range (IQR): 60.5 to 74.7 years]; median left ventricular ejection fraction 26% [IQR: 22% to 32%]) received a median dose of 8.2 million (IQR: 5 to 10 million) hESC-derived cardiovascular progenitors embedded in a fibrin patch that was epicardially delivered during a coronary artery bypass procedure. The primary endpoint was safety at 1 year and focused on: 1) cardiac or off-target tumor, assessed by imaging (computed tomography and fluorine-18 fluorodeoxyglucose positron emission tomography scans); 2) arrhythmias, detected by serial interrogations of the cardioverter-defibrillators implanted in all patients; and 3) alloimmunization, assessed by the presence of donor-specific antibodies. Patients were followed up for a median of 18 months. RESULTS: The protocol generated a highly purified (median 97.5% [IQR: 95.5% to 98.7%]) population of cardiovascular progenitors. One patient died early post-operatively from treatment-unrelated comorbidities. All others had uneventful recoveries. No tumor was detected during follow-up, and none of the patients presented with arrhythmias. Three patients developed clinically silent alloimmunization. All patients were symptomatically improved with an increased systolic motion of the cell-treated segments. One patient died of heart failure after 22 months. CONCLUSIONS: This trial demonstrates the technical feasibility of producing clinical-grade hESC-derived cardiovascular progenitors and supports their short- and medium-term safety, thereby setting the grounds for adequately powered efficacy studies. (Transplantation of Human Embryonic Stem Cell-derived Progenitors in Severe Heart Failure [ESCORT]; NCT02057900).
BACKGROUND: In addition to scalability, human embryonic stem cells (hESCs) have the unique advantage of allowing their directed differentiation toward lineage-specific cells. OBJECTIVES: This study tested the feasibility of leveraging the properties of hESCs to generate clinical-grade cardiovascular progenitor cells and assessed their safety in patients with severe ischemic left ventricular dysfunction. METHODS: Six patients (median age 66.5 years [interquartile range (IQR): 60.5 to 74.7 years]; median left ventricular ejection fraction 26% [IQR: 22% to 32%]) received a median dose of 8.2 million (IQR: 5 to 10 million) hESC-derived cardiovascular progenitors embedded in a fibrin patch that was epicardially delivered during a coronary artery bypass procedure. The primary endpoint was safety at 1 year and focused on: 1) cardiac or off-target tumor, assessed by imaging (computed tomography and fluorine-18 fluorodeoxyglucose positron emission tomography scans); 2) arrhythmias, detected by serial interrogations of the cardioverter-defibrillators implanted in all patients; and 3) alloimmunization, assessed by the presence of donor-specific antibodies. Patients were followed up for a median of 18 months. RESULTS: The protocol generated a highly purified (median 97.5% [IQR: 95.5% to 98.7%]) population of cardiovascular progenitors. One patient died early post-operatively from treatment-unrelated comorbidities. All others had uneventful recoveries. No tumor was detected during follow-up, and none of the patients presented with arrhythmias. Three patients developed clinically silent alloimmunization. All patients were symptomatically improved with an increased systolic motion of the cell-treated segments. One patient died of heart failure after 22 months. CONCLUSIONS: This trial demonstrates the technical feasibility of producing clinical-grade hESC-derived cardiovascular progenitors and supports their short- and medium-term safety, thereby setting the grounds for adequately powered efficacy studies. (Transplantation of Human Embryonic Stem Cell-derived Progenitors in Severe Heart Failure [ESCORT]; NCT02057900).