Elsevier

The Knee

Volume 23, Issue 4, August 2016, Pages 647-654
The Knee

Final results of a phase I–II trial using ex vivo expanded autologous Mesenchymal Stromal Cells for the treatment of osteoarthritis of the knee confirming safety and suggesting cartilage regeneration

https://doi.org/10.1016/j.knee.2015.08.013Get rights and content

Highlights

  • Therapy of knee osteoarthritis with autologous BM derived MSCs is feasible and safe.

  • MSCs intra-joint application improves pain and quality of life of OA patients.

  • Clinical improvement of MSCs treated patients persisted up to four years.

  • Magnetic resonance imaging (MRI) assessment is innovative and have shown signs of cartilage regeneration.

Abstract

Background

Cellular therapies have shown encouraging results in the treatment of chronic osteoarthritis (OA). Herein, we present the final results of a phase I–II clinical trial assessing the feasibility, safety and efficacy of ex vivo expanded autologous bone marrow Mesenchymal Stromal Cells (MSC, XCEL-M-ALPHA), infused intra-articularly, in patients with knee OA.

Methods

Fifteen patients (median age = 52 years) with grade II(9) or III(6) gonarthrosis (Kellgren & Lawrence classification) and chronic pain were treated with an intra-articular infusion of 40.9 × 106 ± 0.4 × 106 MSCin a phase I–II prospective, open-label, single-dose, single-arm clinical trial. Endpoints were safety and tolerability. Efficacy was measured by the Visual Analogue Scale for pain, algofunctional Health Assessment Questionnaire, Quality of Life (QoL) SF-36 questionnaire, Lequesne functional index and WOMAC score. Cartilage integrity was assessed by Magnetic Resonance Imaging and quantitative T2-mapping at 0, 6 and 12 months.

Results

The cell-based product was well tolerated with few reported Adverse Events (mild arthralgia and low back pain). There was a relevant decrease in the intensity of pain since day 8 after the infusion, that was maintained after 12 months. The SF-36 QoL test showed improvement of parameters including bodily pain, role physical and physical functioning at month 12. The health assessment questionnaire revealed a significant decrease of incapacity. Moreover, T2 mapping showed signs of cartilage regeneration in all patients at 12 months post-treatment.

Conclusions

Single intra-articular infusion of XCEL-M-ALPHA is a safe and well-tolerated cell-based product, associated with a long-lasting amelioration of pain, improvement of QoL (up to four years), and signs of cartilage repair.

Introduction

Osteoarthritis (OA) is the first cause of pain, loss of functionality and disability in humans [1], [2]. It is the most prevalent chronic articular disease, accounting for nearly 2% of public health expenses in developed countries thus leading to a decrease in productivity [3], [4]. Multiple therapeutic options have been proposed by the American Association of Orthopedic Surgeons, the American College of Rheumatology and the European League Against Rheumatism, including 1) symptomatic treatment based on pain control, 2) physical and educational therapy, and 3) specific arthrosis-driven therapies such as glucosamine and/or chondroitin sulphate intake [5], [6]. When oral therapy is ineffective, corticosteroid, hyaluronic acid, platelet rich plasma based intra-articular injections or arthroscopic lavage with or without debridement are considered [7], [8], [9]. However, these treatments have demonstrated modest clinical benefits compared to placebo. Articular replacement with prosthesis is recommended as the last therapeutic option. Cell therapy by implantation of ex vivo cultured autologous chondrocytes has been used for the regeneration of focal cartilage defects, although limited formation of new cartilage is attained using this approach [10], [11]. New generation of cell-based medicines employ Mesenchymal Stromal Cells (MSC) for cartilage repair and pain relief [12], [13], [14], [15]. The beneficial effect of MSC in cartilage resurfacing has been well documented in rats [16], rabbits [12], sheep [17], and pigs [18]. In humans, autologous MSC have been administered by intra-articular infusion in case series with encouraging results, particularly regarding sustained pain relief [19], [20].

Herein we report the analysis of a phase I–II prospective clinical trial in 15 patients with mild to moderate knee OA treated with a minimally invasive technique in two-steps and follow up to four years, demonstrating the safety and efficacy of intra-articularly administered bone marrow (BM)-derived MSC (XCEL-M-ALPHA, manufactured under Good Manufacturing Practice, GMP) aiming at long-term control of associated pain but also cartilage regeneration.

Section snippets

Patients, follow up and procedures

A phase I–II prospective, open-label, single-dose, single-arm clinical trial was conducted by Institut de Teràpia Regenerativa Tissular (ITRT) at the Hospital Quirón Teknon (HQT, Barcelona, Spain) with a cell-based therapy product manufactured at XCELIA's GMP facilities (Banc de Sang i Teixits, Barcelona, Spain) from October 2010 to June 2012. HQT's Ethics Committee and the Spanish Agency of Medicines and Medical Devices (AEMPS, Madrid, Spain) approved the clinical trial protocol (EudraCT

Cell expansion

Following a validated GMP-compliant process, MSC were successfully derived from BM and scaled up to generate clinical doses of 40.9 × 106 ± 0.4 × 106 viable MSC in a final volume of 10.0 ± 0.3 mL (n = 15, Table 5). MNC were plated and after seven to 10 days of culture the sample achieved a relatively homogeneous cellularity with a fibroblastic aspect and confluent pattern. This morphology was preserved throughout the 21-day culture period. The phenotypic characteristics of the human MSC were 99.7% ± 0.2%

Discussion

Articular cartilage is a tissue with a very slow turn over and limited regenerative capacity [32]. The potential of MSC to differentiate in vitro into different cellular lineages together with their paracrine properties for reducing inflammation and pain present this type of cells as candidates for use in regenerative therapy [12]. Indeed, MSC have demonstrated in vivo their capacity to survive, home and contribute in the production of extracellular matrix in the articular milieu [16], [17],

Conclusions

The results presented here support the feasibility and safety of the intra-articular infusion of autologous MSC expanded ex vivo complying with GMP standards. Furthermore, treatment with MSC was associated with anti-inflammatory and regenerative outcomes observed in OA knees, which requires further assessment. The current study lacked a control group, randomized clinical trials including a comparator arm, a higher sample size and a longer follow up are desirable in order to confirm safety and

Conflict of interest statement

None.

Acknowledgments

The authors would like to acknowledge Prof. Siegfried Trattnig, Dr. Kai Vilanova and Prof. Joan Sentís for scientific and statistical advice.

MEDCEL project: Development, evaluation and feasibility study of a cell factory for the production of cell drugs as a support for cell, tissue, and organ transplant and regenerative medicine. File No: PSE-010000-2007-4//PSE-010000-2008-4 was funded by the Spanish Ministry of Science and Innovation.

FACTOCEL project: Enlargement of the production facilities

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