A Phase I Dose-Escalation Clinical Trial to Assess the Safety and Efficacy of Umbilical Cord-Derived Mesenchymal Stromal Cells in Knee Osteoarthritis

Abstract

Osteoarthritis (OA) is the most common degenerative joint disease. Mesenchymal stromal cells (MSC) are promising cell-based therapy for OA. However, there is still a need for additional randomized, dose-dependent studies to determine the optimal dose and tissue source of MSC for improved clinical outcomes. Here, we performed a dose-dependant evaluation of umbilical cord (UC)-derived MSC (Celllistem) in a murine model and in knee OA patients. For the preclinical study, a classical dose (200.000 cells) and a lower dose (50.000 cells) of Cellistem were intra-articularly injected into the mice knee joints. The results showed a dose efficacy response effect of Cellistem associated with a decreased inflammatory and degenerative response according to the Pritzker OARSI score. Following the same approach, the dose-escalation phase I clinical trial design included 3 sequential cohorts: low-dose group (2 × 106 cells), medium-dose group (20 × 106), and high-dose group (80 × 106). All the doses were safe, and no serious adverse events were reported. Nonetheless, 100% of the patients injected with the high-dose experienced injection-related swelling in the knee joint. According to WOMAC total outcomes, patients treated with all doses reported significant improvements in pain and function compared with baseline after 3 and 6 months. However, the improvements were higher in patients treated with both medium and low dose as compared to high dose. Therefore, our data demonstrate that the intra-articular injection of different doses of Cellistem is both safe and efficient, making it an interesting therapeutic alternative to treat mild and symptomatic knee OA patients. Trial registration ClinicalTrials.gov NCT03810521.

Keywords: dose escalation; murine OA model; osteoarthritis; phase I clinical trial; umbilical-cord-derived mesenchymal stromal cells.

Graphical Abstract

Figure 1.

Preclinical dose response Cellistem efficacy evaluation in the murine collagenase-induced osteoarthritis model. (A) Experimental design of the dose response preclinical trial in the CIOA murine model. (B) Representative figure showing the different knee areas evaluated for microCT and histological analysis. (C) Representative 3D images of XY axes photography selection evaluated by MicroCT analysis. Bone mineral density average analyses of the (D) medial tibia, (E) lateral tibia, (F) medial femur, and (G) lateral femur. (H) Representative histological images of CIO mice not treated (collagenase) or treated with different doses of Cellistem. Histological OA score analyses of the (I) Medial Tibia, (J) Lateral Tibia, (K) Medial Femur, and (L) Lateral Femur. Results are expressed as bone mineral density (mm³), a histomorphometry analysis of 3D images of articular cartilages and as OA score of histological sections of knee joints of the mice (n = at least 15/group in 3 independent experiments). Results are expressed as the mean ± SD; *P ≤ .05, **P < .01, ***P < .001 (one-way ANOVA-test).

Figure 2.

Biodistribution and immunogenic analysis in vivo of Cellistem. (A) Experimental design of the biodistribution and immunogenic assay in the CIOA murine model. (B) Representative mice images following intra-articular injections with DiR-Cellistem high dose in OA mice (white arrows), evaluated after 0, 7, and 14 days post-treatment by Odyssey CLx Imager. Sodium chloride (NaCl) was used in control OA mice (left images). (C) The percentage of proinflammatory and antiinflamatory T-CD4 cells was analyzed in freshly isolated drained popliteal lymph node was evaluated by FACS analysis. Results represent mean ± SD; *P ≤ .05, **P < .01, ***P < .001. One-way ANOVA test of N = 10 for 2 independent experiments.

Figure 3.

Efficacy clinical outcomes. (A) WOMAC‐A pain subscale. (B) WOMAC‐C function subscale. (C) Total WOMAC. (D) VAS analysis. Abbreviations: LD, low dose (2 × 10⁶ UC-MSC); MD, medium dose (20 × 10⁶ UC-MSC); HD, high dose (80 × 10⁶ UC-MSC). WOMAC, Western Ontario and Mc Master Universities Arthritis Index. VAS, Visual Analogue Scale. Results are presented as mean ± SD and were performed to baseline in each group. *P ≤ .05, **P < .01, ***P < .001.

Figure 4.

Flow chart of the clinical trial.