Administration of Adult Human Bone Marrow-Derived, Cultured, Pooled, Allogeneic Mesenchymal Stromal Cells in Critical Limb Ischemia Due to Buerger's Disease: Phase II Study Report Suggests Clinical Efficacy

Abstract

Critical limb ischemia (CLI) due to Buerger’s disease is a major unmet medical need with a high incidence of morbidity. This phase II, prospective, nonrandomized, open‐label, multicentric, dose‐ranging study was conducted to assess the efficacy and safety of i.m. injection of adult human bone marrow‐derived, cultured, pooled, allogeneic mesenchymal stromal cells (BMMSC) in CLI due to Buerger’s disease. Patients were allocated to three groups: 1 and 2 million cells/kg body weight (36 patients each) and standard of care (SOC) (18 patients). BMMSCs were administered as 40–60 injections in the calf muscle and locally, around the ulcer. Most patients were young (age range, 38–42 years) and ex‐smokers, and all patients had at least one ulcer. Both the primary endpoints—reduction in rest pain (0.3 units per month [SE, 0.13]) and healing of ulcers (11% decrease in size per month [SE, 0.05])—were significantly better in the group receiving 2 million cells/kg body weight than in the SOC arm. Improvement in secondary endpoints, such as ankle brachial pressure index (0.03 [SE, 0.01] unit increase per month) and total walking distance (1.03 [SE, 0.02] times higher per month), were also significant in the group receiving 2 million cells/kg as compared with the SOC arm. Adverse events reported were remotely related or unrelated to BMMSCs. In conclusion, i.m. administration of BMMSC at a dose of 2 million cells/kg showed clinical benefit and may be the best regimen in patients with CLI due to Buerger’s disease. However, further randomized controlled trials are required to confirm the most appropriate dose. Stem Cells Translational Medicine 2017;6:689–699

Concise Review: Multifaceted Characterization of Human Mesenchymal Stem Cells for Use in Regenerative Medicine

“…These cells are enriched for precursor cells that could be efficacious for therapy . Stempeutics Research's specifications for their allogeneic BMMSC product, Stempeucel, includes parameters such as morphology (fibroblastic and spindle‐shaped), cell counts of 180–220 million cells per bag, viability of >85%, ISCT‐defined surface marker levels >80% along with CD166 > 80% and CD133 < 5% as their release criteria for administration . As more strategies evolve and new criteria are published, the selection panel is continuously being developed.…”

Tumor Formation of Adult Stem Cell Transplants in Rodent Arthritic Joints

“…Avoiding ex vivo stem cell expansion appears to be the safest approach, and is implemented in several clinical applications of ADSC mediated bone and cartilage repair [41–44]. ADSC expansion in vitro prior to delivery to the patient is nonetheless common in other conditions such as Buerger’s disease [45, 46], where cells are cultured for several weeks. Culture media may include FBS followed by human serum or enriched serum-free media for clinical use or 5 % human serum alone.…”

“…Culture media may include FBS followed by human serum or enriched serum-free media for clinical use or 5 % human serum alone. ADSC cells may be from a single donor [45] for each recipient or multiple donors [46], which may complicate careful analysis of cell products and safety.…”

Cell Therapy for Chronic Limb-Threatening Ischemia: Current Evidence and Future Directions

“…In vitro and vivo studies have demonstrated that MSC can home to injured tissue and secrete beneficial factors that suppress inflammation and improve angiogenesis via paracrine pathways . Several small exploratory clinical trials showed positive effects of MSCs in the treatment of CLTI compared to standard of care or placebo . Clinical studies that directly compare BM‐MSCs with MNCs for the treatment of CLTI are scarce.…”

“…Therefore larger and better‐designed trials are required to determine the potential added value of novel therapies in CLTI . In the light of these considerations, small phase I/II or pragmatically designed studies have provided valuable first indications about potential efficacy of MSCs in CLTI. However, at no point can they substitute evidence from placebo‐controlled double‐blind randomized trials.…”