Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitors for Severe Ischemic Left Ventricular Dysfunction

Philippe Menasché; Valérie Vanneaux; Albert Hagège; Alain Bel; Bernard Cholley; Alexandre Parouchev; Isabelle Cacciapuoti; Reem Al-Daccak; Nadine Benhamouda; Hélène Blons; Onnik Agbulut; Lucie Tosca; Jean-Hugues Trouvin; Jean-Roch Fabreguettes; Valérie Bellamy; Dominique Charron; Eric Tartour; Gérard Tachdjian; Michel Desnos; Jérôme Larghero

doi:10.1016/j.jacc.2017.11.047

Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitors for Severe Ischemic Left Ventricular Dysfunction

J Am Coll Cardiol. 2018 Jan 30;71(4):429-438. doi: 10.1016/j.jacc.2017.11.047.

Authors

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

Affiliations

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.

PMID: 29389360
DOI: 10.1016/j.jacc.2017.11.047

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).

Keywords: cardiovascular progenitor cells; embryonic stem cells; heart failure; tissue engineering.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Cohort Studies
Coronary Artery Bypass*
Feasibility Studies
Female
Human Embryonic Stem Cells / transplantation*
Humans
Male
Middle Aged
Myocardial Ischemia / complications
Myocardial Ischemia / mortality
Myocardial Ischemia / therapy*
Stem Cell Transplantation / methods*
Survival Rate
Treatment Outcome
Ventricular Dysfunction, Left / complications
Ventricular Dysfunction, Left / mortality
Ventricular Dysfunction, Left / therapy*

Associated data

ClinicalTrials.gov/NCT02057900