Phase 1 Clinical Trial of Autologous Mesenchymal Stem Cell Transplantation in Multiple Sclerosis (IN8-2.003)

Objective: To describe the design and progress of an ongoing Phase 1 group-sequential trial of autologous mesenchymal stem cell (MSC) transplantation in multiple sclerosis (MS). Background 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 a number of human conditions. Published experience in MS is modest. Design/Methods: 24 participants with relapsing forms of MS, Expanded Disability Status Scale (EDSS) 3.0-6.5, clinical or MRI activity in the prior 2 years, and optic nerve involvement will be enrolled. Bone-marrow-derived MSCs are culture-expanded in DMEM / 10% fetal bovine serum / 10 ng/ml human fibroblast growth factor-2 then cryopreserved. After confirmation of release criteria, 1-2x10^6 MSCs/kg are administered IV. The primary outcomes are feasibility, safety, and tolerability with Data Safety Monitoring Committee review after every 4 participants. Exploratory efficacy endpoints comparing 2 months pre-infusion and 6 months post-infusion include relapses, disability (EDSS, MS Functional Composite, low-contrast letter acuity), MRI (T2 lesions, T1 lesions, gadolinium-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 health status. Ancillary immunologic mechanistic studies utilizing peripheral blood mononuclear cells (PBMCs) isolated at several pre- and post-infusion timepoints assess lymphocyte subsets by flow cytometry, T-cell responses to myelin antigens, and T-cell and B-cell regulatory functions. In vitro studies assess the mechanisms of MSC-induced immunomodulation and compare MSC-PBMC interactions in MS patients vs. controls. Results: 4 participants have been infused to date. Culture duration was 21-41 days, yielding cell doses for administration of 2x10^6 MSCs/kg (n=2) and 1.5x10^6 MSCs/kg (n=2). MSC cultures for 2 additional participants are in progress. Conclusions: Target enrollment by April 2012 is 10-12 participants. Updated study status will be presented. Supported by: Department of Defense, National Institutes of Health, Caroline Hurwitz Fund. Disclosure: Dr. Cohen has received personal compensation for activities with Biogen Idec, Eli Lilly & Company, Novartis, and Vaccinex. Dr. Cohen has received research support for activities with Biogen Idec, BioMS, Genzyme Corporation, Novartis, Synthon, and Teva Neuroscience. Dr. Bar-Or has received personal compensation for activities with Aventis Pharmaceuticals, Bayhill Therapeutics, Biogen Idec, Berlex Laboratories, Eli Lilly & Company, Genentech, Inc., GlaxoSmithKline, Ono Pharmaceutical, Diogenix, Roche Diagnostics Corporation, Merck Serono, Novartis, Teva Neuroscience. Dr. Bermel has received personal compensation for activities with Astellas, Biogen Idec, Novartis, and Teva Neuroscience as a consultant and/or speaker. Dr. Fisher has received personal compensation for activities with Biogen Idec. Dr. Fisher has received research support from Biogen Idec and Genzyme. Dr. Fox has received personal compensation for activities with Avanir, Biogen Idec, EMD Serono, and Novartis. Dr. Fox has received research support from Biogen Idec and Genentech, Inc. Dr. Gerson has received (royalty or license fee or contractual rights) payments from Osiris Therapeutics. Dr. Imrey has nothing to disclose. Dr. Lazarus has nothing to disclose. Dr. Planchon has nothing to disclose. Dr. Reese has nothing to disclose. Dr. Schwanger has nothing to disclose. Dr. Skaramagas has nothing to disclose.