The biology of mesenchymal stem cells and the utility of the cellular therapy in Multiple Sclerosis

Multiple Sclerosis (MS) is the commonest cause of neurological disability in young adults and affects about 100 000 people in the UK. Although there are a number of licensed treatment options there remains an urgent need for neuro-protective and reparative strategies. Mesenchymal stem cells (MSCs) represent a heterogeneous population of cells found in a variety of connective tissue of which bone marrow-derived MSCs (BM-MSCs) are the best characterised. They are multi-potent cells which interact with the adaptive and innate immune system either via direct cell contact or release of soluble factors. The mechanisms to induce peripheral tolerance are well described but varied; the clinical relevance of these, however, is not clear. The Stem cells in Rapidly Evolving Active Multiple Sclerosis (STREAMS) trial was a small phase 2, double-blind randomised controlled cross-over trial of a single intravenous dose of 1-2 x 106 BM-MSCs/kg in MS patients whose objective was to evaluate the safety and efficacy of MSCs. It formed part of a wider collaborative study in MS (MESEMS). 13 patients had successful BM harvests with a mean yield of 3.21 x 106 cells/kg (range 1.66 – 6.78 x 106) but a further six failed to reach the required dose and were withdrawn. There were no significant adverse events in the trial. No significant reduction in the relapse rate, changes in disability measurement or patient reported outcomes was observed. Immunological changes detected ex- vivo included a reduced cell frequency of pathogenic cells such as Th1 and CD1c+ mDCs and an increase was noted in B10 regs post-MSC infusion however the study was under-powered to conclude any significant benefit. There was an increase in the level of TSLP in the CSF which warrants further investigation. Preliminary results from MESEMS confirm safety but failed to demonstrate efficacy of MSCs in reducing enhancing lesions on MRI. Overall, we conclude that MSC therapy appears feasible and safe but no significant evidence exists for clinical therapeutic efficacy.Open Acces

Soluble CD27 is an intrathecal biomarker of T-cell-mediated lesion activity in multiple sclerosis

Abstract Objective Soluble CD27 is a promising cerebrospinal fluid inflammatory biomarker in multiple sclerosis. In this study, we investigate relevant immune and neuro-pathological features of soluble CD27 in multiple sclerosis. Methods Protein levels of soluble CD27 were correlated to inflammatory cell subpopulations and inflammatory cytokines and chemokines detected in cerebrospinal fluid of 137 patients with multiple sclerosis and 47 patients with inflammatory and non-inflammatory neurological disease from three independent cohorts. Production of soluble CD27 was investigated in cell cultures of activated T and B cells and CD27-knockout T cells. In a study including matched cerebrospinal fluid and post-mortem brain tissues of patients with multiple sclerosis and control cases, levels of soluble CD27 were correlated with perivascular and meningeal infiltrates and with neuropathological features. Results We demonstrate that soluble CD27 favours the differentiation of interferon-γ-producing T cells and is released through a secretory mechanism activated by TCR engagement and regulated by neutral sphingomyelinase. We also show that the levels of soluble CD27 correlate with the representation of inflammatory T cell subsets in the CSF of patients with relapsing-remitting multiple sclerosis and with the magnitude of perivascular and meningeal CD27 + CD4 + and CD8 + T cell infiltrates in post-mortem central nervous system tissue, defining a subgroup of patients with extensive active inflammatory lesions. Interpretation Our results demonstrate that soluble CD27 is a biomarker of disease activity, potentially informative for personalized treatment and monitoring of treatment outcomes

Safety, tolerability, and activity of mesenchymal stem cells versus placebo in multiple sclerosis (MESEMS): a phase 2, randomised, double-blind crossover trial

Background 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.Methods 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.Findings 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.Interpretation 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. Copyright (C) 2021 Elsevier Ltd. All rights reserved

Safety, tolerability, and activity of mesenchymal stem cells versus placebo in multiple sclerosis (MESEMS): a phase 2, randomised, double-blind crossover trial

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

Additional file 1 of Soluble CD27 is an intrathecal biomarker of T-cell-mediated lesion activity in multiple sclerosis

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