Intravenous Infusion of Umbilical Cord Blood‐Derived Mesenchymal Stem Cells in Rheumatoid Arthritis: A Phase Ia Clinical Trial
Stem Cells Translational Medicine
STEM CELLS TRANSLATIONAL MEDICINE 2018;7:636–642 www.StemCellsTM.com
EUN HYE PARK ,a HEE -SUK LIM ,b SEUNGHEE LEE ,c KYOUNGHWAN ROH ,c KWANG -WON SEO ,c KYUNG -SUN KANG ,c,d KICHUL SHINb
Based on immunomodulatory actions of human umbilical cord blood‐derived mesenchymal stem cells (hUCB‐MSCs), in vitro or preclinical studies of hUCB‐MSCs have been conducted extensively in rheumatoid arthritis (RA). However, few human trials have investigated the outcomes of hUCB‐MSC infusions. The CURE‐iv trial was a phase I, uncontrolled, open label trial for RA patients with moderate disease activity despite treatment with methotrexate. The patients received a single intravenous infusion of 2.5 × 107, 5 × 107, or 1 × 108 cells of hUCB‐MSCs for 30 minutes, three patients in each cluster, with an increment of cell numbers when there was no dose‐limited adverse event. Clinical and safety assessments were performed during the study period, and serum cytokines were measured at baseline and 24 hours after the infusion. Out of 11 screened RA patients, 9 were enrolled. The participants were predominantly female (78%) and the mean age was 57.4 years. The mean disease duration was 9.5 years, and baseline 28‐joint disease activity score (DAS28; using erythrocyte sedimentation rate) was 4.53. There was no major toxicity in all clusters up to 4 weeks after the infusion. Serum erythrocyte sedimentation rate changes at 4 weeks (n = 9) were −7.9 ± 10.4 (p = .0517) and DAS28 changes were −1.60 ± 1.57 (p = .0159). Reduced levels of IL‐1β, IL‐6, IL‐8, and TNF‐α at 24 hours were observed in the cluster infused with 1 × 108 MSCs. This phase Ia hUCB‐MSC infusion trial for established RA patients revealed no short‐term safety concerns.
This is the first phase Ia study of RA patients that evaluated the safety and tolerability of a single intravenous infusion with hUCB‐MSCs and with cell numbers of up to 1 × 108, revealing an acceptable safety profile. Conclusions regarding efficacy in phase I trials are limited, and although evaluation of disease activity was not the primary objective of this study, a single infusion of hUCB‐MSCs effectively reduced the mean DAS28 at week 4. Considering favorable safety profiles, intravenous infusion of hUCB‐MSCs may constitute a therapeutic option for patients with RA, who are refractory to or intolerant of MTX. There is a wide array of opportunities for future clinical studies with different hUCB‐MSC infusion strategies in which safety profiles should be carefully monitored and outcome measures further refined for optimized effectiveness evaluations.