Safety and preliminary efficacy of allogeneic bone marrow-derived multipotent mesenchymal stromal cells for systemic sclerosis: a single-centre, open-label, dose-escalation, proof-of-concept, phase 1/2 study.

Journal

The Lancet. Rheumatology
ISSN: 2665-9913
Titre abrégé: Lancet Rheumatol
Pays: England
ID NLM: 101765308

Informations de publication

Date de publication:
Feb 2022
Historique:
received: 11 08 2021
revised: 01 10 2021
accepted: 04 10 2021
medline: 1 2 2022
pubmed: 1 2 2022
entrez: 30 1 2024
Statut: ppublish

Résumé

Systemic sclerosis remains an orphan life-threatening autoimmune disease. The unique immunomodulatory, proangiogenic, and antifibrotic properties of mesenchymal stromal cells provide a strong rationale for mesenchymal stromal cell-based therapy for systemic sclerosis, and treatment with mesenchymal stromal cells has shown benefits in preclinical models of this disease. The safety of allogeneic bone marrow-derived mesenchymal stromal cell administration in patients with severe systemic sclerosis has not yet been established. We aimed to test the safety and feasibility of a single intravenous injection of intrafamilial allogeneic bone marrow-derived mesenchymal stromal cells to treat severe diffuse systemic sclerosis. We did an open-label, dose-escalation, proof-of-concept, phase 1/2 study at Saint-Louis-Hospital, Paris, France. Eligible patients were aged 18-70 years with severe diffuse systemic sclerosis, who fulfilled the 2013 American College of Rheumatology and European League Against Rheumatism systemic sclerosis criteria, had a minimum modified Rodnan skin score of 15 (range 0-51), had severe lung, heart, or kidney involvement, and had inadequate response or contraindications to conventional immunosuppressive therapy or autologous haematopoietic stem cell transplantation. Patients with severe comorbidities were excluded. The first ten recipients were to receive a single intravenous infusion of 1 × 10 Between March 24, 2014, and Jan 6, 2020, 20 cisgender individuals (13 women and seven men) with severe diffuse systemic sclerosis were enrolled. All 20 patients were included in the primary outcome analysis. No infusion-related severe adverse events and three infusion-related adverse events occurred in the first 10 days after treatment; one patient had grade 1 flushing and another patient had grade 1 nausea and grade 2 asthenia. After ten days and up to a median follow-up of 24·1 months (IQR 20·8-24·5), 36 non-treatment-related severe adverse events in 14 (70%) patients and no treatment-related adverse event were reported. A single infusion of allogeneic bone marrow-derived mesenchymal stromal cells was safe in patients with severe diffuse systemic sclerosis. Future placebo-controlled trials will help to definitively ascertain the efficacy of mesenchymal stromal cell-based cell therapy from various tissue sources in larger number of patients with systemic sclerosis. French Ministry of Health, Capucine Association, Fonds de Dotation de l'AFER pour la Recherche Médicale, and Agence Nationale de la Recherche (Infrastructure Program Ecell), France.

Sections du résumé

BACKGROUND BACKGROUND
Systemic sclerosis remains an orphan life-threatening autoimmune disease. The unique immunomodulatory, proangiogenic, and antifibrotic properties of mesenchymal stromal cells provide a strong rationale for mesenchymal stromal cell-based therapy for systemic sclerosis, and treatment with mesenchymal stromal cells has shown benefits in preclinical models of this disease. The safety of allogeneic bone marrow-derived mesenchymal stromal cell administration in patients with severe systemic sclerosis has not yet been established. We aimed to test the safety and feasibility of a single intravenous injection of intrafamilial allogeneic bone marrow-derived mesenchymal stromal cells to treat severe diffuse systemic sclerosis.
METHODS METHODS
We did an open-label, dose-escalation, proof-of-concept, phase 1/2 study at Saint-Louis-Hospital, Paris, France. Eligible patients were aged 18-70 years with severe diffuse systemic sclerosis, who fulfilled the 2013 American College of Rheumatology and European League Against Rheumatism systemic sclerosis criteria, had a minimum modified Rodnan skin score of 15 (range 0-51), had severe lung, heart, or kidney involvement, and had inadequate response or contraindications to conventional immunosuppressive therapy or autologous haematopoietic stem cell transplantation. Patients with severe comorbidities were excluded. The first ten recipients were to receive a single intravenous infusion of 1 × 10
FINDINGS RESULTS
Between March 24, 2014, and Jan 6, 2020, 20 cisgender individuals (13 women and seven men) with severe diffuse systemic sclerosis were enrolled. All 20 patients were included in the primary outcome analysis. No infusion-related severe adverse events and three infusion-related adverse events occurred in the first 10 days after treatment; one patient had grade 1 flushing and another patient had grade 1 nausea and grade 2 asthenia. After ten days and up to a median follow-up of 24·1 months (IQR 20·8-24·5), 36 non-treatment-related severe adverse events in 14 (70%) patients and no treatment-related adverse event were reported.
INTERPRETATION CONCLUSIONS
A single infusion of allogeneic bone marrow-derived mesenchymal stromal cells was safe in patients with severe diffuse systemic sclerosis. Future placebo-controlled trials will help to definitively ascertain the efficacy of mesenchymal stromal cell-based cell therapy from various tissue sources in larger number of patients with systemic sclerosis.
FUNDING BACKGROUND
French Ministry of Health, Capucine Association, Fonds de Dotation de l'AFER pour la Recherche Médicale, and Agence Nationale de la Recherche (Infrastructure Program Ecell), France.

Identifiants

DOI: 10.1016/S2665-9913(21)00326-X PMID: 38288741
pubmed: 38288741
pii: S2665-9913(21)00326-X
doi: 10.1016/S2665-9913(21)00326-X
pii:
doi:

Banques de données

ClinicalTrials.gov
['NCT02213705']

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

e91-e104

Informations de copyright

Copyright © 2022 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests We declare no competing interests.

Auteurs

Dominique Farge (D)

Unité de Médecine Interne (UF 04) CRMR MATHEC, Maladies Auto-Immunes et Thérapie Cellulaire, Centre de Référence des Maladies Auto-Immunes Systémiques Rares d'Ile-de-France MATHEC, AP-HP, Hôpital St-Louis, Paris, France; Université de Paris, IRSL, Recherche Clinique Appliquée À L'Hématologie, EA3518, Paris, France; Department of Medicine, McGill University, Montreal, QC, Canada; Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada. Electronic address: dominique.farge-bancel@aphp.fr.

Séverine Loisel (S)

SITI, CHU Rennes, Etablissement Français du Sang Bretagne, Rennes, France; UMR 1236, Université Rennes, INSERM, Etablissement Français du Sang Bretagne, Rennes, France.

Matthieu Resche-Rigon (M)

SBIM, Hôpital Saint-Louis, APHP, Paris, France.

Pauline Lansiaux (P)

Unité de Médecine Interne (UF 04) CRMR MATHEC, Maladies Auto-Immunes et Thérapie Cellulaire, Centre de Référence des Maladies Auto-Immunes Systémiques Rares d'Ile-de-France MATHEC, AP-HP, Hôpital St-Louis, Paris, France; Université de Paris, IRSL, Recherche Clinique Appliquée À L'Hématologie, EA3518, Paris, France.

Ines Colmegna (I)

Department of Medicine, McGill University, Montreal, QC, Canada; Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.

David Langlais (D)

Department of Human Genetics, McGill University, Montreal, QC, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada; McGill University Genome Center, McGill Research Centre on Complex Traits, Montreal, QC, Canada.

Catney Charles (C)

Unité de Médecine Interne (UF 04) CRMR MATHEC, Maladies Auto-Immunes et Thérapie Cellulaire, Centre de Référence des Maladies Auto-Immunes Systémiques Rares d'Ile-de-France MATHEC, AP-HP, Hôpital St-Louis, Paris, France; Université de Paris, IRSL, Recherche Clinique Appliquée À L'Hématologie, EA3518, Paris, France.

Grégory Pugnet (G)

Service de Médecine Interne et Immunologie Clinique Pôle Hospitalo-Universitaire des Maladies Digestives, CHU Rangueil, Toulouse, France.

Alexandre Thibault Jacques Maria (ATJ)

Department of Internal Medicine-Multi-organ Diseases, Montpellier School of Medicine, Saint-Eloi University Hospital, University of Montpellier, Montpellier, France.

Emmanuel Chatelus (E)

Rheumatology, CHU Strasbourg, Centre National de Référence des Maladies Auto-Immunes et Systémiques Rares Est/Sud-Ouest (RESO), Strasbourg, Alsace, France.

Thierry Martin (T)

Department of Clinical Immunology, Hôpitaux Universitaires de Strasbourg, Centre National de Référence des Maladies Auto-Immunes et Systémiques Rares Est/Sud-Ouest (RESO), Strasbourg, Alsace, France.

Eric Hachulla (E)

Department of Internal Medicine and Clinical Immunology, National Reference Center for Rare Systemic Autoimmune Diseases North and North-West of France, Claude Huriez Hospital, Lille University, Lille, France.

Vissal David Kheav (VD)

Laboratory of Immunology and Histocompatibility, AP-HP St-Louis Hospital, Paris, France.

Nathalie C Lambert (NC)

INSERM UMRs 1097 Arthrites Autoimmunes, Aix Marseille University, Marseille, France.

HanChen Wang (H)

Department of Human Genetics, McGill University, Montreal, QC, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada; McGill University Genome Center, McGill Research Centre on Complex Traits, Montreal, QC, Canada.

David Michonneau (D)

Université de Paris, IRSL, Recherche Clinique Appliquée À L'Hématologie, EA3518, Paris, France; Service d'Hématologie-Greffe, AP-HP, Hôpital Saint-Louis, Institut de Recherche Saint-Louis, Paris, France.

Christophe Martinaud (C)

Centre de Transfusion Sanguine des Armées, Clamart, Ecell France, Clamart, France.

Luc Sensebé (L)

EFS Pyrénées-Méditerranée, INSERM U1031, UMR STROMALab (CNRS/EFS/INSERM), Université Paul Sabatier, Toulouse, France.

Audrey Cras (A)

Cell Therapy Unit, AP-HP, Saint Louis Hospital, Paris, France; Université de Paris, INSERM UMR1140, Paris, France; INSERM, CIC de Biothérapies CBT501, Paris, France.

Karin Tarte (K)

SITI, CHU Rennes, Etablissement Français du Sang Bretagne, Rennes, France; UMR 1236, Université Rennes, INSERM, Etablissement Français du Sang Bretagne, Rennes, France.

Classifications MeSH