Abstract
Inflammatory bowel disease (IBD), namely, Crohn's disease and ulcerative colitis,
remains a grievous and recalcitrant problem incurring significant human and health
care costs, even in consideration of the growing incidence. Initial goals of care
aimed to achieve the induction and maintenance of clinical remission. The advent of
novel treat-to-target approaches using patient stratification, early introduction
of immunosuppressants and rapid escalation to biologics or early use of combination
therapy has refocused the goals of care toward the achievement of mucosal healing.
This is in an attempt to preserve intestinal function, decrease hospitalization and
surgery rates and improve the quality of life of affected patients. Cellular therapeutics
for the treatment of IBD offers an unprecedented opportunity to change the current
paradigm from single-targeted to systems-targeted therapy, trying to dampen the whole
inflammatory cascade instead of a only molecule. Therefore, as we move forward, the
importance of designing informative and possibly adaptive trial designs, standardizing
methodologies, harmonizing goals of therapy and evaluating methods cannot be underemphasized.
In this article, we review the current literature on the application of mesenchymal
stromal cells for the treatment of IBD in an effort to establish a consensus on designing
efficient and consistent clinical trials for the intravenous use of this cellular
therapy in IBD.
Key Words
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References
- Crohn's Disease and Ulcerative Colitis - From Epidemiology and Immunobiology to a Rational Diagnostic and Therapeutic Approach.2nd edition. Springer Nature, New York2017
- Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies.Lancet. 2018; 390: 2769-2778https://doi.org/10.1016/S0140-6736(17)32448-0
- Cancers complicating inflammatory bowel disease.N Engl J Med. 2015; 372: 1441-1452https://doi.org/10.1056/NEJMra1403718
- Converging goals of treatment of inflammatory bowel disease from clinical trials and practice.Gastroenterology. 2015; 148: 37-51https://doi.org/10.1053/j.gastro.2014.08.003
- The expenditures for academic inpatient care of inflammatory bowel disease patients are almost double compared with average academic gastroenterology and hepatology cases and not fully recovered by diagnosis-related group (DRG) proceeds.PLoS One. 2016; 11e0147364https://doi.org/10.1371/journal.pone.0147364
- Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target.Am J Gastroenterol. 2015; 110: 1324-1338https://doi.org/10.1038/ajg.2015.233
- A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group.N Engl J Med. 1997; 337: 1029-1035
- Systematic review with meta-analysis: comparative efficacy of immunosuppressants and biologics for reducing hospitalisation and surgery in Crohn's disease and ulcerative colitis.Aliment Pharmacol Ther. 2017; 45: 3-13https://doi.org/10.1111/apt.13847
- Inflammatory bowel disease (IBD) pharmacotherapy and the risk of serious infection: a systemic review and network analysis.BMC Gastroenterology. 2017; 17: 52https://doi.org/10.1186/s12876-017-0602-0
- Loss of response and need for adalimumab dose intensification in Crohn's disease: a systematic review.Am J Gastroenterol. 2011; 106: 674-684https://doi.org/10.1038/ajg.2011.60
- Tofacitinib as induction and maintenance therapy for ulcerative colitis.N Engl J Med. 2017; 377: 496-497https://doi.org/10.1056/NEJMc1707500
- Next generation of small molecules in inflammatory bowel disease.Gut. 2016; 66: 199-209https://doi.org/10.1136/gutjnl-2016-31291213
- Mesenchymal stem cells: a new strategy for immunosuppression and tissue repair.Cell Res. 2010; 20: 510-518https://doi.org/10.1038/cr.2010.44
- Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis.Am J Respir Crit Care Med. 2010; 182: 1047-1057https://doi.org/10.1164/rccm.201001-0010OC
- Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial.Lancet. 2016; 388: 1281-1290https://doi.org/10.1016/S0140-6736(16)31203-X
- Mesenchymal stem cells as an immunomodulatory therapeutic strategy for autoimmune diseases.AUtoimmun Rev. 2011; 10: 410-415https://doi.org/10.1016/j.autrev.2011.01.005
- Mesenchymal stromal cells: sensors and switchers of inflammation.Cell Stem Cell. 2013; 13: 392-402https://doi.org/10.1016/j.stem.2013.09.006
- Mesenchymal stromal cells and the innate immune response.Immunol Lett. 2015; 168: 140-146https://doi.org/10.1016/j.imlet.2015.05.004
- Mesenchymal cells recruit and regulate T regulatory cells.Exp Hematol. 2008; 36: 309-318https://doi.org/10.1016/j.exphem.2007.11.007
- Mesenchymal stem cells direct the immunological fate of macrophages.Results Probl Cell Differ. 2017; 62: 61-72https://doi.org/10.1007/978-3-319-54090-0_4
- Immunopathogenesis of IBD: current state of the art.Nat Rev Gastroenterol Hepatol. 2016; 13: 13-27https://doi.org/10.1038/nrgastro.2015.186
- Pathogen- and danger-associated molecular patterns and the cytokine response in sepsis.Surg Infect. 2018; 19: 107-116https://doi.org/10.1089/sur.2017.264
- Evaluating mesenchymal stem cell therapy for sepsis with preclinical meta-analyses prior to initiating a first-in-human trial.Elife. 2016; 5 (pii: e17850)https://doi.org/10.7554/eLife.17850
- Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production.Nat Med. 2009; 15: 42-49https://doi.org/10.1038/nm.1905
- Network analysis of transcriptional responses induced by mesenchymal stem cell treatment of experimental sepsis.Am J Pathol. 2012; 181: 1681-1692https://doi.org/10.1016/j.ajpath.2012.08.009
- Human mesenchymal stem cells reduce mortality and bacteremia in gram-negative sepsis in mice in part by enhancing the phagocytic activity of blood monocytes.Am J Physiol Lung Cell Mol Physiol. 2012; 302: L1003-L1013https://doi.org/10.1152/ajplung.00180.2011
- Mesenchymal stem cells enhance NOX2-dependent reactive oxygen species production and bacterial killing in macrophages during sepsis.Eur Respir J. 2018; 51 (pii: 1702021)https://doi.org/10.1183/13993003.02021-2017
- Inactivated mesenchymal stem cells maintain immunomodulatory capacity.Stem Cells Dev. 2016; 25: 1342-1354https://doi.org/10.1089/scd.2016.0068
- Apoptotic cell clearance: basic biology and therapeutic potential.Nat Rev Immunol. 2014; 14: 166-180https://doi.org/10.1038/nri3607
- Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation.Sci Transl Med. 2017; 9 (pii: eaam7828)https://doi.org/10.1126/scitranslmed.aam7828
- Mesenchymal stromal cells: clinical challenges and therapeutic opportunities.Cell Stem Cell. 2018; 22: 824-833https://doi.org/10.1016/j.stem.2018.05.004
- Mesenchymal stem cells reduce colitis in mice via release of TSG6, independently of their localization to the intestine.Gastroenterology. 2015; 149 (e20): 163-176https://doi.org/10.1053/j.gastro.2015.03.013
- Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses.Gastroenterology. 2009; 136: 978-989https://doi.org/10.1053/j.gastro.2008.11.041
- Mesenchymal stem cell expression of interleukin-35 protects against ulcerative colitis by suppressing mucosal immune responses.Cytotherapy. 2018; 20: 911-918https://doi.org/10.1016/j.jcyt.2018.05.004
- Early injection of human adipose tissue-derived mesenchymal stem cell after inflammation ameliorates dextran sulfate sodium-induced colitis in mice through the induction of M2 machrophages and regulatory T cells.Cell Tissue Res. 2019; 376: 257-271https://doi.org/10.1007/s00441-018-02981-w
- Adipose-derived mesenchymal stromal cells induce immunomodulatory macrophages which protect from experimental colitis and sepsis.Gut. 2013; 62: 1131-1141https://doi.org/10.1136/gutjnl-2012302152
- Mesenchymal stem cell therapy in necrotizing enterocolitis: a rat study.Pediatr Res. 2011; 70: 489-494https://doi.org/10.1203/PDR.0b013e31822d7ef2
- Mesenchymal stem cell therapy stimulates endogenous host progenitor cells to improve colonic epithelial regeneration.PLoS ONE. 2013; 8: e70170https://doi.org/10.1371/journal.pone.0070170
- Adoptive transfer of mesenchymal stromal cells accelerates intestinal epithelium recovery of irradiated mice in an interleukin-6-dependent manner.Cytotherapy. 2012; 14: 1164-1170https://doi.org/10.3109/14653249.2012.684378
- Mesenchymal stem cells increase self-renewal of small intestinal epithelium and accelerate structural recovery after radiation injury.Adv Exp Med Biol. 2006; 585: 19-30
- Anti-fibrogenic potential of mesenchymal stromal cells in treating fibrosis in Crohn's disease.Dig Dis Sci. 2018; 63: 1821-1834https://doi.org/10.1007/s10620-018-5082-8
- Forming research questions.J Clin Epidemiol. 2006; 59: 881-886https://doi.org/10.1016/j.jclinepi.2006.06.006
- GRADE guidelines: 2. Framing the question and deciding on important outcomes.J Clin Epidemiol. 2011; 64: 395-400https://doi.org/10.1016/j.jclinepi.2010.09.012
- Utilization of the PICO framework to improve searching PubMed for clinical questions.BMC Med Inform Decis Mak. 2007; 7: 16https://doi.org/10.1186/1472-6947-7-16
- Association between framing of the research question using the PICOT format and reporting quality of randomized controlled trials.BMC Med Res Methodol. 2010; 10: 11https://doi.org/10.1186/1471-2288-10-11
- AUtologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn's disease: results of a phase I study.Gut. 2010; 59: 1662-1669https://doi.org/10.1136/gut.2010.215152
- Development of a Crohn's disease activity index: national cooperative Crohn's disease study.Gastroenterology. 1976; 70: 439-444
- Allogeneic mesenchymal stem cell transplantation in seven patients with refractory inflammatory bowel disease.Gut. 2012; 61: 468-469https://doi.org/10.1136/gutjnl-2011-300083
- Safety and tolerability of human placenta-derived cells (PDA001) in treatment-resistant Crohn's disease: a phase 1 study.Inflamm Bowel Dis. 2013; 19: 754-760https://doi.org/10.1097/MIB.0b013e31827f27df
- A new measure of health status for clinical trials in inflammatory bowel disease.Gastroenterology. 1989; 96: 804-810
- Human placenta-derived cells (PDA-001) for the treatment of moderate-to-severe Crohn's disease: a phase 1b/2a study.Inflamm Bowel Dis. 2015; 21: 1809-1816https://doi.org/10.1097/MIB.0000000000000441
- Intravascular mesenchymal stromal/stem cell therapy product diversification: time for new clinical guidelines.Trends Mol Med. 2019; 25: 149-163https://doi.org/10.1016/j.molmed.2018.12.006
- A phase 2 study of allogeneic mesenchymal stromal cells for luminal Crohn's disease refractory to biologic therapy.Clin Gastroenterol Hepatol. 2014; 12: 64-71https://doi.org/10.1016/j.cgh.2013.06.021
- The safety of autologous and metabolically fit bone marrow mesenchymal stromal cells in medically refractory Crohn's disease – a phase 1 trial with three doses.Aliment Pharmacol Ther. 2016; 44: 471-481https://doi.org/10.1111/apt.13717
- Cryopreserved or fresh mesenchymal stromal cells: only a matter of taste or key to unleash the full clinical potential of MSC therapy?.Adv Exp Med Biol. 2016; 951: 77-98https://doi.org/10.1007/978-3-319-45457-3_7
- Do cryopreserved mesenchymal stromal cells display impaired immunomodulatory and therapeutic properties?.Stem Cells. 2014; 32: 2430-2442https://doi.org/10.1002/stem.1729
- Umbilical cord mesenchymal stem cell treatment for Crohn's disease: a randomized controlled clinical trial.Gut Liver. 2018; 12: 73-78https://doi.org/10.5009/gnl17035
- Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials.PLoS One. 2012; 7: e47559https://doi.org/10.1371/journal.pone.0047559
- Concise review: a safety assessment of adipose-derived cell therapy in clinical trials: a systematic review of reported adverse events.Stem Cells Transl Med. 2017; 6: 1786-1794https://doi.org/10.1002/sctm.17-0031
- Defining severity in inflammatory bowel disease.Gastroenterol Hepatol. 2015; 11: 474-476
- Biomarker enrichment strategies: matching trial design to biomarker credentials.Nat Rev Clin Oncol. 2014; 11: 81-90https://doi.org/10.1038/nrclinonc.2013.218
- Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis.J Clin Invest. 2011; 121: 4170-4179https://doi.org/10.1172/JCI59255
- Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology.Can J Gastroenterol. 2005; : 5-36
- The first European evidence-based consensus on extra-intestinal manifestations in inflammatory bowel disease.J Crohn Colitis. 2016; 10: 239-254https://doi.org/10.1093/ecco-jcc/jjv213
- A simple index of Crohn's-disease activity.Lancet. 1980; 1: 514
- A simple clinical colitis activity index.Gut. 1998; 43: 29-32
- Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of ulcerative colitis: randomized trials.Br Med J. 1989; 298: 82-86
- Development and validation of an endoscopic index of the severity for Crohn's disease: a prospective multicentre study. Groupe d'Etudes Therapeutiques des Affections Inflammatoires du Tube Digestif (GETAID).Gut. 1989; 30: 983-989
- Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD.Gastrointest Endosc. 2004; 60: 505-512
- Validation of the ulcerative colitis colonoscopic index of severity and its correlation with disease activity measures.Clin Gastroenterol Hepatol. 2013; 11: 49-54https://doi.org/10.1016/j.cgh.2012.08.003
- Accuracy of magnetic resonance enterography in assessing response to therapy and mucosal healing in patients with Crohn's disease.Gastroenterology. 2014; 146: 374-382https://doi.org/10.1053/j.gastro.2013.10.055
- Diagnostic accuracy of magnetic resonance colonography for the evaluation of disease activity and severity in ulcerative colitis: a prospective study.Gut. 2013; 62: 1566-1572https://doi.org/10.1136/gutjnl-2012-303240
- Development of the NIH Patient-Reported Outcomes Measurement Information System (PROMIS) gastrointestinal symptom scales.Am J Gastroenterol. 2014; 109: 1804-1814https://doi.org/10.1038/ajg.2014.237
- Development and validation of a rapid, generic measure of disease control from the patient's perspective: the IBD-control questionnaire.Gut. 2014; 63: 1092-1102https://doi.org/10.1136/gutjnl-2013-305600
- Concise review: multipotent mesenchymal stromal cells in blood.Stem Cells. 2007; 25: 69-77https://doi.org/10.1634/stemcells.2006-0335
- The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine.Nat Med. 2013; 19: 35-42https://doi.org/10.1038/nm.3028
- Tissue factor as a link between inflammation and coagulation.Trends Cardiovasc Med. 2016; 26: 297-303https://doi.org/10.1016/j.tcm.2015.12.001
- Different procoagulant activity of therapeutic mesenchymal stromal cells derived from bone marrow and placental decidua.Stem Cells Dev. 2015; 24: 2269-2279https://doi.org/10.1089/scd.2015.0120
- Clinical cellular therapeutics accelerate clot formation.Stem Cells Transl Med. 2018; 7: 731-739https://doi.org/10.1002/sctm.18-0015
- Is the intravascular administration of mesenchymal stem cells safe? Mesenchymal stem cells and intravital microscopy.Microvasc Res. 2009; 77: 370-376https://doi.org/10.1016/j.mvr.2009.02.001
- Fate of culture-expanded mesenchymal stem cells in the microvasculature: in vivo observations of cell kinetics.Circ Res. 2009; 104: 398-402https://doi.org/10.1161/CIRCRESAHA.108.187724
- Are therapeutic human mesenchymal stromal cells compatible with human blood?.Stem Cells. 2012; 30: 1565-1574https://doi.org/10.1002/stem.1111
- Tissue factor triggers procoagulation in transplanted mesenchymal stem cells leading to thromboembolism.Biochem Biophys Res Commun. 2013; 431: 203-209https://doi.org/10.1016/j.bbrc.2012.12.134
- Thromboembolism induced by umbilical cord mesenchymal stem cell infusion: a report of two cases and literature review.Transplant Proc. 2017; 49: 1656-1658https://doi.org/10.1016/j.transproceed.2017.03.078
- Intravenous infusion of human adipose mesenchymal stem cells modifies the host response to lipopolysaccharide in humans: a randomized, single-blind, parallel group, placebo controlled trial.Stem Cells. 2018; 36: 1778-1788https://doi.org/10.1002/stem.2891
- Adipose mesenchymal stromal cells isolated from type 2 diabetic patients display reduced fibrinolytic activity.Diabetes. 2013; 62: 4266-4269https://doi.org/10.2337/db13-0896
- Do ABO blood group antigens hamper the therapeutic efficacy of mesenchymal stromal cells?.PLoS One. 2014; 9: e85040https://doi.org/10.1371/journal.pone.0085040
- The COMET Handbook: version 1.0.Trials. 2017; 18: 280
- A taxonomy has been developed for outcomes in medical research to help improve knowledge discover.J Clin Epidemiol. 2018; 96: 84-92https://doi.org/10.1016/j.jclinepi.2017.12.020
- Challenges to the design, execution, and analysis of randomized controlled trials for inflammatory bowel disease.Gastroenterology. 2012; 143: 1461-1469https://doi.org/10.1053/j.gastro.2012.09.031
- Development of a core outcome set for clinical trials in inflammatory bowel disease: study protocol for a systematic review of the literature and identification of a core outcome set using a Delphi survey.BMJ Open. 2017; 7e016146https://doi.org/10.1136/bmjopen-2017-016146
- Developing a standard set of patient-centred outcomes for inflammatory bowel disease-an international, cross-disciplinary consensus.J Crohns Colitis. 2018; 12: 408-418https://doi.org/10.1093/ecco-jcc/jjx161
- Endpoints for clinical trials evaluating disease modification and structural damage in adults with Crohn's disease.Inflamm Bowel Dis. 2009; 15: 1599-1604https://doi.org/10.1002/ibd.21034
- Development of the Crohn's disease digestive damage score, the Lemann score.Inflamm Bowel Dis. 2011; 17: 1415-1422https://doi.org/10.1002/ibd.21506
- Reproducibility of histological assessments of disease activity in UC.Gut. 2015; 64: 1765-1773https://doi.org/10.1136/gutjnl-2014-307536
- The quality of life questionnaire EQ-5D-5L: psychometric properties and normative values for the general German population.Qual Life Res. 2014; 23: 443-447https://doi.org/10.1007/s11136-013-0498-2
- Health-related quality of life in patients with inflammatory bowel disease measured with the short form-36: psychometric assessments and a comparison with general population norms.Inflamm Bowel Dis. 2005; 11: 909-918
- Development of the Patient Activation Measure (PAM): conceptualizing and measuring activation in patients and consumers.Health Serv Res. 2004; 39: 1005-1026https://doi.org/10.1111/j.1475-6773.2004.00269.x
- Validity, reliability, and responsiveness of the work productivity and activity impairment questionnaire in Crohn's disease.Clin Ther. 2008; 30: 393-404https://doi.org/10.1016/j.clinthera.2008.02.016
- How to apply the International Classification of Functioning, Disability and Health (ICF) for rehabilitation management in clinical practice.Eur J Phys Rehabil Med. 2008; 44: 329-342
- Validation of the Inflammatory Bowel Disease Disability Index in a population-based cohort.Gut. 2017; 66: 588-596https://doi.org/10.1136/gutjnl-2015-310151
- Best practices for conducting economic evaluations in health care: a systematic review of quality assessment tools.Agency for Healthcare Research and Quality (US), RockvilleMD2012
- Hematopoietic stem cell transplantation in Crohn's disease: state-of-the-art treatment.Dig Dis. 2017; 35: 107-114https://doi.org/10.1159/000449090
- Thymic output generates new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients.J Exp Med. 2005; 201: 805-816https://doi.org/10.1084/jem.20041679
- Mesenchymal stem cells: emerging mechanisms of immunomodulation and therapy.World J Stem Cells. 2014; 6: 526-539https://doi.org/10.4252/wjsc.v6.i5.526
- Safety of allogeneic bone marrow derived mesenchymal stromal cell therapy in renal transplant recipients: the neptune study.J Transl Med. 2015; 13: 344https://doi.org/10.1186/s12967-015-0700-0
- Mesenchymal stromal cell infusions as rescue therapy for corticosteroid-refractory adult autoimmune enteropathy.Mayo Clin Proc. 2012; 87: 909-914https://doi.org/10.1016/j.mayocp.2012.04.014
- A refractory celiac patient successfully treated with mesenchymal stem cell infusions.Mayo Clin Proc. 2016; 91: 812-819https://doi.org/10.1016/j.mayocp.2016.03.001
- Assessing response and loss of response to biological therapies in IBD.Am J Gastroenterol. 2011; 106: 685-698https://doi.org/10.1038/ajg.2011.103
Article info
Publication history
Published online: June 11, 2019
Accepted:
May 25,
2019
Received:
April 30,
2019
Identification
Copyright
© 2019 International Society for Cell and Gene Therapy. Published by Elsevier Inc. All rights reserved.
