Thursday, 2 October 2014

ACTRIMS 2014 mesenchymal stem cells

What happened at ACTRIMS 2014 with regard to mesenchymal stem cells you asked so here are the abstracts

VK Harris, T Vyshkina, S Chirls, SA Sadiq

Intrathecal administration of mesenchymal stem cell-neural progenitors in multiple sclerosis: an interim analysis of a phase I clinical trial

Background: Cell-based therapies with regenerative potential are an emerging therapeutic strategy for treating disability associated with progressive MS. Mesenchymal stem cell-neural progenitors (MSC-NPs) are an autologous bone marrow-derived population of regenerative cells currently under investigation as a novel MS treatment targeting CNS repair and regeneration. In preclinical studies in mouse EAE, we established that intrathecal (IT) delivery of MSC-NPs given in three separate doses was associated with cell migration to lesion areas, suppression of local inflammatory response, and trophic support for damaged cells at the lesion site. These pathological features were associated with improvement in clinical scores of EAE. The initial clinical experience with IT administration of autologous MSC-NPs in seven MS patients also supported the dosing, safety, feasibility, and potential efficacy of this therapeutic approach. Based on these promising pre-clinical and early clinical data, the FDA approved the initiation of a phase I clinical trial investigating IT autologous MSC-NPs in 20 patients with MS.
Objectives: To evaluate safety, tolerability, and preliminary efficacy of three IT administrations of autologous MSC-NPs in patients with progressive MS.
Methods: The study is a 20 patient, open-label, phase I clinical study of autologous MSC-NPs administered IT in three doses of up to 10 million cells per injection, spaced three months apart. Pre-administration quality testing of autologous MSC-NPs expanded from bone marrow aspirates included analysis of sterility, purity, identity, and chromosomal stability. Primary safety outcomes include adverse event assessments. Secondary outcomes to observe trends in efficacy include neurological exam, MRI, evoked potentials, and urodynamics testing.
Results: The study enrolled 20 MS patients with established disability (average EDSS 6.0, range 3.5 to 8.5) and relatively stable disease as evidenced by less than 1.0 point change in EDSS in the last year, and stable MRI disease burden with no enhancing lesions in the last six months. Bone marrow MSCs from all study subjects were isolated, expanded, and tested according to release criteria. Preliminary safety outcomes in the first five study subjects indicate safety and tolerability of the treatment.
Conclusions: The MSC-NP trial is the first of its kind to test IT administration of neural progenitors as a regenerative therapy for MS.

Phase I trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis 
JA Cohen, PB Imrey, SM Planchon, RA Bermel, E Fisher, RJ Fox, A Bar-Or, SL Sharp, TT Skaramagas, P Jagodnik, M Karafa, S Morrison, J Reese Koc, SL Gerson, HM Lazarus

Background: Mesenchymal stem cells (MSCs) have potent immunomodulatory, tissue-protective, and repair-promoting properties in vitro and in animal models. Clinical trials support the safety and efficacy of MSC transplantation in several human conditions. Published experience in multiple sclerosis (MS) is modest.
Objectives: To assess feasibility, safety, tolerability, and efficacy of autologous mesenchymal stem cell MSC transplantation in MS.
Methods: 24 participants with relapsing forms of MS, Expanded Disability Status Scale (EDSS) 3.0-6.5, clinical or radiographic disease activity in the prior 2 years, and optic nerve involvement were enrolled. Bone-marrow-derived MSCs were culture-expanded in low glucose DMEM containing 10% fetal bovine serum and 10 ng/ml human fibroblast growth factor-2, then cryopreserved. After confirmation of release criteria, 1-2x106 MSCs/kg were thawed and administered IV. Primary outcomes were feasibility, safety, and tolerability with Data Safety Monitoring Committee review after every 4 participants. Relapses, EDSS, MS Functional Composite, low-contrast letter acuity, MRI (T2 lesions, T1 lesions, gadolinium [Gd]-enhancing lesions, whole brain and gray matter atrophy, diffusion tensor imaging, and magnetization transfer imaging), optical coherence tomography, visual evoked potentials, and patient self-reported global health status were monitored serially for 2 months pre- and 6 months post-infusion to explore efficacy. Peripheral blood mononuclear cells were isolated at 2 pre- and 3 post-infusion times for ancillary immunologic mechanistic studies.
Results: 2 patients withdrew pre-infusion due to culture failure and Gd allergy, respectively, and were replaced. We infused 16 women and 8 men, 10 relapsing-remitting and 14 secondary progressive MS, mean age 46.5 and EDSS 5.2, and 25% with Gd-enhancing brain lesions. Mean cell dosage (requiring 1-3 passages) was 1.9x106 MSCs/kg (range 1.3-2.0)  with post-thaw viability ≥95%. Cell infusion was well tolerated. There were no treatment-related severe or serious adverse events. All planned clinical, imaging, and laboratory assessments were performed (except 1  blood test). Neither disease activation nor significant improvement was observed. Detailed exploratory analyses of efficacy measures and immunologic mechanistic studies are ongoing.
Conclusions: This Phase I trial supports the feasibility, safety, and tolerability of autologous MSC transplantation in MS. Future trials adequately powered to assess efficacy more definitively are warranted.

Immune function monitoring in a phase I trial of autologous culture-expanded mesenchymal stem cell transplantation for relapsing multiple sclerosis
A Bar-Or, M-N Boivin, A Rozenberg, T Johnson, C Belabani, G Morisse, J Sirois, S Lai Wing Sun, S Vanamala, A Del Rosario Villalobos, J Reese Koc, S Morrison, RA Bermel, PB Imrey, SM Planchon, JA Cohen
Mesenchymal stem cells (MSCs) have immunomodulatory, tissue-protective, and repair-promoting properties in vitro and in animal models, but human MSCs paradoxically induce in vitro Th17 responses by human peripheral blood mononuclear cells (PBMCs) under some conditions. Published data on in vivo immune effects of MSC transplantation are limited.
Objectives: To assess in vivo immunological effects of a single dose of autologous MSCs administered intravenously in patients with relapsing forms of multiple sclerosis (MS).
Methods: In a single-arm open-label Phase I trial of a single IV infusion of  autologous culture-expanded MSCs for relapsing forms of MS, PBMCs were isolated and cryopreserved, using strict SOPs, from 22 of 24 participants twice before and twice after (Months -1, 0, 1, and 3) MSC infusion. Entry criteria included Expanded Disability Status Scale (EDSS) 3.0-6.5, and clinical or radiographic disease activity in the prior 2 years. Mean MSC cell dosage was 1.9x106 MSC/kg (range 1.3-2.0) requiring 1-3 passages; post-thaw viability ≥95%. The primary immunological outcomes were the treatment-associated changes in percent of Th1 and Th17 CD4+ T cell responses within activated PBMCs measured by flow cytometry and intracellular cytokine staining. Overall proliferation (tritiated thymidine incorporation) and cytokine secretion (ELISA) of activated PBMCs were also assessed.
Results: 15 women and 7 men, mean age 46.4, participated, 8 with relapsing-remitting and 14 with secondary progressive MS, 27.2% with baseline enhancing brain lesions, and mean EDSS 5.4. MSC infusion was tolerated well with no treatment-related severe or serious adverse events. Neither disease activation nor significant improvement in new disease activity was observed. PBMC recoveries (generally >80%) and viabilities (generally >90%) did not differ between visits or between pre- and post-infusion samples. Variability was high, but an estimated 16% increase in the percentage of CD4+IL17+ T cells from the aggregated two pre-infusion visits to the Month 1 post treatment visit (95% confidence interval: -2% to +36%; p=0.08) was followed by an estimated 19% drop (2% to 33%; p=0.03) to former levels. PBMC proliferation curves rose slightly at Month 1 (3.3×103 across doses, p=0.04).
Conclusions: Though not definitive, these data are consistent with possible  augmentation of Th17 responses by MSC transplantation in some MS patients. This potentially adverse consequence should be monitored in future trials.

Publications on the UK

Aleixandre-Benavent R, Alonso-Arroyo A, González de Dios J, Vidal-Infer A, González-Muñoz M, Sempere AP. Bibliometric profile of the global scientific research on multiple sclerosis (2003-2012).Mult Scler. 2014 Sep. pii: 1352458514540357. [Epub ahead of print]

BACKGROUND AND OBJECTIVES:The aim of this paper is to analyse the scientific research on multiple sclerosis using a bibliographic analysis of articles published during the period 2003-2012.
METHODS:The items under study were obtained from the Science Citation Index-Expanded (SCI-E) database, which was accessed through the Web of Science (WOS) platform. All records with the term 'multiple sclerosis' in the title, plus all articles published in the journals Multiple Sclerosis and Multiple Sclerosis Journal, were analysed.
RESULTS:A total of 9778 articles, with 160,966 citations, were retrieved on multiple sclerosis, and the majority of the articles were published in Multiple Sclerosis Journal (n = 1511). The articles were published in journals belonging to 135 different subject areas, with the greatest number of papers falling under the category of clinical neurology. The countries that published the largest numbers of articles were the United States (US) (n = 2786), Italy (n = 1263), the United Kingdom (n = 1147) and Germany (n = 1018). International collaborations produced 20.4% of the papers.
CONCLUSIONS: We emphasise the progressive growth of publications worldwide, the publication of articles in a wide variety of journals covering numerous subject areas, and the research leadership of Western countries, most notably European countries, the US and Canada.

UK slipping

Long-term effect of Copaxone

This retrospective cohort study from Spain aims to analyse the long term outcomes of patients on Copaxone. 

The main headline findings are the following

  • 85% of patients remained free from disability progression (as measured by EDSS)
  • Stable EDSS over the study period (i.e. no significant change from the beginning to the end of the period)
  • Reduction in annual relapse rate 
  • Reduction in T1 Gadolinium enhancing lesions

What does all this mean?

Well at first glance, if I were on Copaxone I would feel pretty reassured by this data but there are a number of factors to consider when looking at the small print. 

Firstly, this study was funded by Teva. Who are Teva I here you ask? Well they are the manufacturers of Copaxone with a vested interest in demonstrating the efficacy of their drug. 

Secondly, (see my previous post on cohort studies) this is a retrospective observational study which comes with its own limitations - we are relying on case note review which is often unreliable

Thirdly, there is no control group to compare with which can be problematic

The study defines 'clinical effectiveness' as being disability free for 5 years but we must remember the natural history of MS - it can take many years to go from RRMS to SPMS and therefore these people may have been simply captured early in their disease course. This becomes more relevant when one thinks about the fact by 9 years follow-up, the study only had data on less than 50% of the cohort.

The MRI data is also a cause for concern - comparing Gd-enhancing lesions from onset of treatment to last date of follow up is deceptive; these lesions do not represent long term acquired disability but recent areas of inflammation. Indeed, we would expect less of these in any case at the later stages of MS as relapses tail off and disability builds up. 

All in all, this is an interesting study, however I would have liked to have seen it done by an independent group who did not have a vested interest in Copaxone. 

Arnal-García C, Amigo-Jorrin MD, López-Real AM, Lema-Devesa C, Llopis N, Rosa RS; XPERIENCIA-5 Study Group. Long-term effectiveness of glatiramer acetate in clinical practice conditions.

J Clin Neurosci. 2014 Sep. pii: S0967-5868(14)00490-1. doi: 10.1016/j.jocn.2014.05.045. [Epub ahead of print]

Glatiramer acetate currently represents one of the main treatments for relapsing-remitting multiple sclerosis (RRMS). However, the information available about its long-term effect in clinical practice is still limited. Thus, this multicenter retrospective cohort study aimed to assess the long-term effectiveness of glatiramer acetate in this setting. 

The study population included RRMS patients treated with glatiramer acetate for at least 5years after its marketing authorization and the primary endpoint was long-term clinical effectiveness, defined as absence of disability progression for at least five consecutive years. A total of 149 patients were included into the study, who had received glatiramer acetate for a mean of 6.9±1.4years (5years, n=149; 6years, n=112; 7years, n=63; 8years, n=32; 9years, n=21). 
More than 85% of patients remained free from disability progression through years 1 to 9 of glatiramer acetate treatment, and 75.2% showed absence of disability progression for at least five consecutive years. Expanded Disability Status Scale (EDSS) scores were maintained, with most patients showing stable/improved EDSS and 92.6% sustaining EDSS <6. Decreased annual relapse rates and increased proportion of relapse-free patients were maintained during the whole glatiramer acetate treatment compared to the year prior to its authorization (p<0.001). The number of gadolinium-enhanced T1-weighted lesions also decreased from pre-glatiramer-acetate assessment to last follow-up whilst on glatiramer acetate (p<0.05). 
In conclusion, administration of glatiramer acetate shows long-term clinical effectiveness for RRMS treatment; its effect under clinical practice conditions slowed disability progression and reduced relapse occurrence for up to 9years.