Highlights
- •Human mesenchymal stem cells have anti-inflammatory and immunomodulatory properties.
- •Preclinical models of CF show mesenchymal stem cells attenuate pulmonary inflammation.
- •Mesenchymal stem cells were safe and well-tolerated in this phase 1 clinical trial.
Abstract
Background
Mesenchymal stem cells are of particular interest in cystic fibrosis (CF) as a potential
therapeutic. Data from pre-clinical studies suggest that allogeneic bone marrow-derived
human mesenchymal stem cells (hMSCs) may provide a new therapeutic treatment for CF
lung disease by attenuating pulmonary inflammation while decreasing bacterial growth
and enhancing antibiotic efficacy.
Methods
Fifteen adults with CF were enrolled in a phase 1 dose-escalation trial of a single
intravenous infusion of hMSCs derived from bone marrow aspirates obtained from a single
pre-clinically validated healthy volunteer donor. The study employed a 3+3 dose escalation
design with subjects receiving a single, intravenous dose of either 1×106, 3×106, or 5×106 hMSCs/kg. Subjects were monitored inpatient for 24 hours and by outpatient visits
and telephone calls for 12 months after the infusion. Safety and tolerability were
evaluated by monitoring symptoms, patient reported outcome questionnaires, adverse
events (AEs), physical exam findings, spirometry, and analyses of safety laboratories.
Preliminary evidence for potential efficacy using inflammatory markers in the blood
and sputum were also evaluated.
Results
No dose-limiting toxicities, deaths or life-threatening adverse events were observed.
Most AEs and serious adverse events (SAEs) were consistent with underlying CF. Vital
signs, physical exam findings, spirometry and safety laboratory results showed no
significant change from baseline. No trends over time were seen in serum or sputum
inflammatory markers nor with clinical spirometry.
Conclusion
Allogeneic hMSC intravenous infusions were safe and well-tolerated in this phase 1
study and warrant additional clinical testing as a potential therapeutic for CF lung
disease.
Keywords
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References
- Cystic fibrosis.Am J Respir Crit Care Med. 1996; 154: 1229-1256
- Inflammation and its genesis in cystic fibrosis.Pediatr Pulmonol. 2015; 50: S39-S56
- Dysregulated cytokine production in human cystic fibrosis bronchial epithelial cells.Inflammation. 2001; 25: 145-155
- Proinflammatory cytokine responses to P. aeruginosa infection in human airway epithelial cell lines.Am J Physiol Lung Cell Mol Physiol. 2001; 280: L493-L502
- Quantitation of inflammatory responses to bacteria in young cystic fibrosis and control patients.Am J Respir Crit Care Med. 1999; 160: 186-191
- Early pulmonary infection, inflammation, and clinical outcomes in infants with cystic fibrosis.Pediatr Pulmonol. 2001; 32: 356-366
- Infection is not required for mucoinflammatory lung disease in CFTR-knockout ferrets.Am J Respir Crit Care Med. 2018; 197: 1308-1318
- Inflammation in cystic fibrosis: an update.Pediatr Pulmonol. 2018; 53: S30-S50
- Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del Allele.N Engl J Med. 2019; 381: 1809-1819
- Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis.Am J Respir Crit Care Med. 2014; 190: 175-184
- Restoring cystic fibrosis transmembrane conductance regulator function reduces airway bacteria and inflammation in people with cystic fibrosis and chronic lung infections.Am J Respir Crit Care Med. 2017; 195: 1617-1628
- Six-year follow-up of ivacaftro-treated subjects with CFTR-G551D: an update on the Dublin cohort.Pediatr Pulmonol. 2019; 54: 334
- Mesenchymal stem cell therapy in lung disorders: pathogenesis of lung diseases and mechanism of action of mesenchymal stem cell.Exp Lung Res. 2013; 39: 315-327
- Lights and shadows in the use of mesenchymal stem cells in lung inflammation, a poorly investigated topic in cystic fibrosis.Cells. 2019; 9
- Optimization of human mesenchymal stem cells for rheumatoid arthritis: implications for improved therapeutic outcomes.ACR Open Rheumatol. 2021;
- Promising role for mesenchymal stromal cells in coronavirus infectious disease-19 (COVID-19)-related severe acute respiratory syndrome?.Blood Rev. 2021; 46100742
- Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37.Stem Cells. 2010; 28: 2229-2238
- Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine.Exp Mol Med. 2013; 45: e54
- Advances in mesenchymal stem cell therapy for immune and inflammatory diseases: use of cell-free products and human pluripotent stem cell-derived mesenchymal stem cells.Stem Cells Transl Med. 2021; 10: 1288-1303
- Cell based therapy aides in infection and inflammation resolution in the murine model of cystic fibrosis lung disease.Stem Cell Discovery. 2013; 3: 139-153
- Antimicrobial properties of mesenchymal stem cells: therapeutic potential for cystic fibrosis infection, and treatment.Stem Cells Int. 2016; 20165303048
- Enhancing cystic fibrosis immune regulation.Front Pharmacol. 2021; 12573065
- Mesenchymal stem cell soluble mediators and cystic fibrosis.J Stem Cell Res Ther. 2017; 7
- Donor-defined mesenchymal stem cell antimicrobial potency against nontuberculous mycobacterium.Stem Cells Transl Med. 2021; 10: 1202-1216
- Consensus International Council for Commonality in Blood Banking Automation-International Society for Cell & Gene Therapy statement on standard nomenclature abbreviations for the tissue of origin of mesenchymal stromal cells.Cytotherapy. 2021; 23: 1060-1063
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.
- Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The pulmozyme study group.N Engl J Med. 1994; 331: 637-642
- Differential effects of the cystic fibrosis lung inflammatory environment on mesenchymal stromal cells.Am J Physiol Lung Cell Mol Physiol. 2020; 319: L908-L925
- Biological considerations in scaling up therapeutic cell manufacturing.Front Pharmacol. 2020; 11: 654
Article info
Publication history
Published online: December 20, 2022
Accepted:
December 3,
2022
Received in revised form:
November 25,
2022
Received:
August 1,
2022
Publication stage
In Press Corrected ProofIdentification
Copyright
© 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
