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.

Please read the comments


  1. At first glance, seems to me that all this studies loose their supposed efficacy during animal to human transition....
    Your opinion profs.?

  2. Lost in translation....I am not sure I agree. First I think we are comparing chalk with cheese.

    In animal models studies are usually in chemical demyelination models, which would naturally repair and so the drugs are only speeding up something that would largely happen but there is no chronic demyelination and gliosis. This can occur in EAE but surprisingly this is not how the stem cells are delivered in studies reported so far. They are given shortly before or at the time of demyelination not long after demyelination is given. Therefore are the human trials attempting to translate what is done in animals...not really. Human studies would need to give treatment at the time the damage is developing or the animal studies would need to deliver treatment to long established chronic demyelination.

    I think the abstracts above do indicate that this is not a miraculous cure. This is clear and this sobering current reality needs to temper the hype, These trials are in response to the media hype and people pressure, but perhaps we are running before we can walk or even crawl. However you can argue that we need to start and the sooner the better, but if we get failures will this impact what is done in the future. Gene therapy was the last great hope but where is it now?. Early rushed trials killed a few people. For stem cells in MS. How do we do a repair trial to show an effect?-it took years to work out how to find a DMT...I suspect early repair trials could have this problem. Which is the best cell type to transplant? How do we control what they will do? Should we be transplanting in or get what;s there to do its job? What is the best group of MSer to show an effect, etc. etc. How long do trials need to be. So it the stem cells work and regrow how long do we need to have a trial. In peripheral nerves that do regrow it could take years to grow.

    Lost in translation...In my opinion the animal data in EAE is not that impressive in contrast to the hype. There is often only a small inhibition of clinical disease severity in EAE however animals are still getting disease and the effect is not that great, In comparison to a standard immunosuppressive. These drugs can wipe out disease completely and if given suboptimally so they get disease If we look for remyelination after the immunosuppression after a standard immunosuppressive that may not even get into the brain, then you get repair. So just as good as stem cells.

    In many studies very few cells ever reach the brain and again the majority of cells may be dead within a week and they are not turning in to myelinating cells or nerves. So if immunosuppression is all that is happening then there are cheaper ways of doing this. In our hands the immunosuppressive action of these types of cell is pants.

    I accept that there looks to be some good effects in some rodent studies. Are these cells going to be immunosuppressive in humans the trials are ongoing.

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