Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells, have been proposed as a promising therapeutic option for people with multiple sclerosis on the basis of their immunomodulatory ...and neuroprotective properties. The MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) study was devised to evaluate the safety, tolerability, and activity of autologous MSCs derived from bone marrow and infused intravenously in patients with active multiple sclerosis.
MESEMS is a randomised phase 2 trial done at 15 sites in nine countries. Patients (aged 18–50 years) with active relapsing-remitting or progressive multiple sclerosis were included if they had a disease duration of 2–15 years since onset of multiple sclerosis and an Expanded Disability Status Scale score of 2·5–6·5. Patients were randomly assigned (1:1), according to a crossover design, to receive a single intravenous dose of autologous bone marrow-derived MSCs followed by placebo at week 24, or to receive placebo followed by autologous MSCs at week 24, with a follow-up visit at week 48. Primary objectives were to test safety and activity of MSC treatment. The primary safety endpoint was to assess the number and severity of adverse events within each treatment arm. The primary efficacy endpoint was the number of gadolinium-enhancing lesions (GELs) counted over week 4, 12, and 24 compared between treatment groups. The primary efficacy endpoint was assessed in the full analyis set, after all participants completed the week 24 visit. Efficacy endpoints were evaluated using a predefined statistical testing procedure. Safety was monitored throughout the study by recording vital signs and adverse events at each visit.
From July 16, 2012, until July 31, 2019, 144 patients were randomly assigned to first receive early intravenous infusion of autologous bone marrow-derived MSCs (n=69) or placebo (n=75). MSC treatment did not meet the primary endpoint of efficacy on the total number of GELs accumulated from baseline to week 24 (rate ratio RR 0·94, 95% CI 0·58–1·50; p=0·78). 213 adverse events were recorded, similarly distributed between groups (93 cases recorded in 35 51% of 69 patients treated first with MSCs vs 120 cases in 42 56% of 75 patients infused first with placebo). The most frequent adverse events reported were infection and infestations, with a total of 54 (25%) of 213 adverse events (18 19% of 93 in the early-MSC group and 36 30% of 120 in the delayed-MSC group). Nine serious adverse events were reported in seven patients treated with placebo versus none in the MSC group. All serious adverse events were considered to be unrelated to the treatment infusion. No deaths were reported during the study.
Bone marrow-derived MSC treatment was safe and well tolerated but did not show an effect on GELs, an MRI surrogate marker of acute inflammation, in patients with active forms of multiple sclerosis, at week 24. Thus, this study does not support the use of bone marrow-derived MSCs to treat active multiple sclerosis. Further studies should address the effect of MSCs on parameters related to tissue repair.
Fondazione Italiana Sclerosi Multipla (FISM), the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), and the Multiple Sclerosis International Federation (MSIF) for centralised activities. Individual trials participating in the MESEMS network are funded by the following agencies: FISM and Compagnia di San Paolo (Italy); The Danish Multiple Sclerosis Society, The Toyota Foundation, and Danish Blood Donors’ Research Foundation (Denmark); the Spanish Health Research Institute Carlos 3 and the Andalusian Public Foundation Progreso y Salud (Spain); the Royan Institute for Stem Cell Biology and Technology (Iran); the Spinal Cord Injury and Tissue Regeneration Centre Salzburg, Paracelsus Medical University, and Salzburg (Austria); the Fondation pour l’aide à la recherche sur la sclérose en plaques (ARSEP), French Muscular Dystrophy Association (AFM)-Telethon (France); the UK Multiple Sclerosis Society and the UK Stem Cell Foundation (UK); and the Multiple Sclerosis Society of Canada and The Multiple Sclerosis Scientific Research Foundation and Research Manitoba (Canada).
This Special Issue, entitled “Personalized Diagnosis and Therapy for Multiple Sclerosis” encompasses eight publications that we consider relevant, because their reading will help the clinician ...working regularly with people who suffer from multiple sclerosis (MS) ...
Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease of the central nervous system. Current therapies decrease the frequency of relapses and limit, to some extent, but do not prevent ...disease progression. Hence, new therapeutic approaches that modify the natural course of MSneed to be identified. Tolerance induction to self‐antigens using monocyte‐derived dendritic cells (MDDCs) is a promising therapeutic strategy in autoimmunity. In this work, we sought to generate and characterize tolerogenic MDDCs (tolDCs) from relapsing‐remitting (RR) MSpatients, loaded with myelin peptides as specific antigen, with the aim of developing immunotherapeutics for MS. MDDCs were generated from both healthy‐blood donors and RR‐MSpatients, and MDDCmaturation was induced with a proinflammatory cytokine cocktail in the absence or presence of 1α,25‐dihydroxyvitamin‐D3, a tolerogenicity‐inducing agent. tolDCs were generated from monocytes of RR‐MSpatients as efficiently as from monocytes of healthy subjects. The RR‐MStolDCs expressed a stable semimature phenotype and an antiinflammatory profile as compared with untreated MDDCs. Importantly, myelin peptide‐loaded tolDCs induced stable antigen‐specific hyporesponsiveness in myelin‐reactive T cells from RR‐MS patients. These results suggest that myelin peptide‐loaded tolDCs may be a powerful tool for inducing myelin‐specific tolerance in RR‐MS patients.
Summary
Aims
Fingolimod, an orally active immunomodulatory drug for relapsing‐remitting multiple sclerosis (RRMS), sequesters T cells in lymph nodes through functional antagonism of the ...sphingosine‐1‐phosphate receptor, reducing the number of potential autoreactive cells that migrate to the central nervous system. However, not all RRMS patients respond to this therapy. Our aim was to test the hypothesis that by immune‐monitoring RRMS patient's leukocyte subpopulations it is possible to find biomarkers associated with clinical response to fingolimod.
Methods
Prospective study. Analysis of peripheral blood mononuclear cell subpopulations by multiparametric flow cytometry, at baseline and +1, +3, +6, +12 months of follow‐up in 40 RRMS patients starting fingolimod therapy.
Results
Fingolimod treatment induced a severe lymphopenia affecting mainly T and B cells. A relative increase in Treg (memory Treg: 3.8 ± 1.0% baseline vs 8.8 ± 4.4% month +1; activated Treg: 1.5 ± 0.7% baseline vs 3.7 ± 2.1% month +1, P < 0.001) as well as transitional B cells (10.5 ± 12.3% baseline vs 18.7 ± 14.6% month +1, P < 0.001) was observed.
Interestingly, lymphocyte subpopulations were already at baseline significantly different in responder patients. The percentage of recent thymic emigrants (RTE) used to stratify fingolimod responder, and no responder patients was the best biomarker (4.0 ± 1.4% vs 7.4 ± 1.9%, respectively P < 0.001).
Conclusion
The results support that immune‐monitoring of lymphocyte subpopulations in peripheral blood is a promising tool to select RRMS candidate for fingolimod treatment.
Background and purpose
This study assessed the effect of patient characteristics on the response to disease‐modifying therapy (DMT) in multiple sclerosis (MS).
Methods
We extracted data from 61,810 ...patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow‐up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12‐month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics.
Results
Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio HR = 0.52, 95% confidence interval CI = 0.45–0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41–0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09–1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity.
Conclusions
DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.
Aim
Dimethyl fumarate (DMF) is one of the most promising therapies for relapsing‐remitting multiple sclerosis (RRMS) patients since it has shown immunomodulatory and neuroprotective effects. However, ...a percentage of RRMS patients do not exhibit an optimal response to DMF. The objective of this study was to identify early biomarkers of treatment response by analyzing changes in peripheral leukocyte subpopulations directly in whole blood samples.
Methods
A longitudinal and prospective study analyzing peripheral blood leukocyte subpopulations in 22 RRMS patients before initiating DMF treatment (baseline) and at 1, 3, 6, and 12 months of follow‐up was performed. Differences between no evidence of disease activity (NEDA) and ongoing disease activity (ODA) patients were analyzed.
Results
The beneficial effect of DMF was associated with a specific depletion of memory CD4+ and CD8+ T lymphocytes and B cells. Importantly, only NEDA patients showed (a) a shift from a pro‐ to an antiinflammatory profile, with an increase of Th2 cells and a decrease of Th1‐like Th17 lymphocytes; and (b) an increase of regulatory CD56bright NK cells.
Conclusion
The optimal response to DMF is mediated by a shift to antiinflammatory and immunoregulatory profile, which puts forward Th1‐like Th17 lymphocytes as a potential early biomarker of treatment response.
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system with a degenerative component, leading to irreversible disability. Mesenchymal stem cells (MSC) have been shown to ...prevent inflammation and neurodegeneration in animal models of MS, but no large phase II clinical trials have yet assessed the exploratory efficacy of MSC for MS.
This is an academic, investigator-initiated, randomized, double-blind, placebo-compared phase I/II clinical trial with autologous, bone-marrow derived MSC in MS. Enrolled subjects will receive autologous MSC at either baseline or at week 24, through a cross-over design. Primary co-objectives are to test safety and efficacy of MSC treatment compared to placebo at 6 months. Secondary objectives will evaluate the efficacy of MSC at clinical and MRI levels. In order to overcome funding constraints, the MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) study has been designed to merge partially independent clinical trials, following harmonized protocols and sharing some key centralized procedures, including data collection and analyses.
Results will provide patients and the scientific community with data on the safety and efficacy of MSC for MS. The innovative approach utilized to obtain funds to support the MESEMS trial could represent a new model to circumvent limitation of funds encountered by academic trials.
Andalusia: NCT01745783 , registered on Dec 10, 2012. Badalona: NCT02035514 EudraCT, 2010-024081-21. Registered on 2012. Canada: ClinicalTrials.gov, NCT02239393 . Registered on September 12, 2014. Copenhagen: EudraCT, 2012-000518-13 . Registered on June 21, 2012. Italy: EudraCT, 2011-001295-19, and ClinicalTrials.gov, NCT01854957 . Retrospectively registered on May 16, 2013. London: Eudra CT 2012-002357-35, and ClinicalTrials.gov, NCT01606215 . Registered on May 25, 2012. Salzburg: EudraCT, 2015-000137-78 . Registered on September 15, 2015. Stockholm: ClinicalTrials.gov, NCT01730547 . Registered on November 21, 2012. Toulouse: ClinicalTrials.gov, NCT02403947 . Registered on March 31, 2015.
Summary
Background
Treatment with tolerogenic dendritic cells (TolDC) is a promising, cell‐based strategy to regulate autoimmune diseases such as multiple sclerosis (MS) in an antigen‐specific way. ...This technique involves the use of TolDC from MS patients cultured in the presence of vitamin D3 (VitD3) and pulsed with myelin peptides to induce a stable hyporesponsiveness in myelin‐specific autologous T cells.
Aim
The purpose of this study was to analyze the in vivo effect of VitD3‐TolDC treatment on experimental autoimmune encephalomyelitis, an animal model of MS.
Methods
Bone marrow‐derived TolDC cultured in the presence of VitD3 and pulsed with peptide 40–55 of the myelin oligodendrocyte glycoprotein (MOG40–55) were administrated preventively, preclinically, and therapeutically to EAE‐induced mice.
Results
We found that VitD3‐TolDC‐MOG treatment showed a beneficial effect, not only decreasing the incidence of the disease but also reducing the severity of the clinical signs mediated by induction of regulatory T cells (Treg), as well as IL‐10 production and reduction of Ag‐specific lymphoproliferation. Our results support VitD3‐TolDC‐peptide(s) treatment as a potential strategy to restore tolerance in autoimmune diseases such as MS.
Objective We present a case of multiple tumefactive demyelinating lesions (TDLs) emerging 24 months after the second cycle of alemtuzumab treatment. Methods A woman with relapsing-remitting multiple ...sclerosis (MS) discontinued fingolimod treatment due to gestational desire, which resulted in a severe disease exacerbation. Alemtuzumab was initiated, accompanied by regular clinical, radiological, and immunological monitoring. Results She relapsed prior to the second cycle, exhibiting 12 T1Gd + lesions, and peripheral blood showed an increase in B-cells and a decrease in T-cells. At 24 months following the second cycle, she developed cognitive impairment and multiple T1Gd + lesions, including TDLs, were evident on the brain MRI. We found not only an increase in B-cells but also in Th1 central memory cells. Th1/Th17 cells increased 3 months before the detection of TDLs. Conclusions TDLs can appear 24 months after the second cycle of alemtuzumab treatment in MS. The increase in Th1/Th17 cells could be a candidate biomarker for TDLs in alemtuzumab-treated MS patients.
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