Autologous mesenchymal stromal cells embedded with Tissucol Duo® for prevention of air leak after anatomical lung resection: results of a prospective phase I/II clinical trial with long-term follow-up.

BACKGROUND: Prolonged air leak (PAL) is the most frequent complication after pulmonary resection. Several measures have been described to prevent the occurrence of PAL in high-risk patients, however, the potential role of mesenchymal stem cells (MSCs) applied in the parenchymal suture line to prevent postoperative air leak in this setting has not been fully addressed. OBJECTIVE: To analyse the feasibility, safety and potential clinical efficacy of the implantation of autologous MSCs embedded in Tissucol Duo® as a prophylactic alternative to prevent postoperative prolonged air leak after pulmonary resection in high-risk patients. STUDY DESIGN: Phase I/II single-arm prospective clinical trial. METHODS: Six patients with high risk of PAL undergoing elective pulmonary resection were included. Autologous bone marrow-derived MSCs were expanded at our Good Manufacturing Practice (GMP) Facility and implanted (embedded in a Tissucol Duo® carrier) in the parenchymal suture line during pulmonary resection surgery. Patients were monitored in the early postoperative period and evaluated for possible complications or adverse reactions. In addition, all patients were followed-up to 5 years for clinical outcomes. RESULTS: The median age of patients included was 66 years (range: 55-70 years), and male/female ratio was 5/1. Autologous MSCs were expanded in five cases, in one case MSCs expansion was insufficient. There were no adverse effects related to cell implantation. Regarding efficacy, median air leak duration was 0 days (range: 0-2 days). The incidence of PAL was nil. Radiologically, only one patient presented pneumothorax in the chest X-ray at discharge. No adverse effects related to the procedure were recorded during the follow-up. CONCLUSIONS: The use of autologous MSCs for prevention of PAL in patients with high risk of PAL is feasible, safe and potentially effective. TRIAL REGISTRATION NO: EudraCT: 2013-000535-27. CLINICALTRIALS: gov idenfier: NCT02045745.

Autologous mesenchymal stem cell transplantation for spinal fusion: 10 years follow-up of a phase I/II clinical trial.

Posterolateral spinal fusion is the standard surgical approach for patients with degenerative disc disease. In our previously published article, we reported a 5-years follow-up of a phase I/II clinical trial in patients undergoing spinal fusion with autologous mesenchymal stem cells (MSCs) embedded in tricalcium phosphate. In the current manuscript, we have updated the results with a 10-year follow-up, the longest reported to date in this setting. After clinical and radiological evaluation, safety of the procedure was further confirmed in all 11 treated patients, with no evidence of tumor, infection, inflammatory reaction, or heterotopic ossification related to the administration of MSCs. Regarding clinical efficacy, low back pain and radicular pain (both assessed by the visual analogue scale-VAS), and the Owestry Disability Index remained significantly lower compared to pre-intervention. Radiologic evaluation demonstrated spinal fusion in all cases, improving over time. Finally, quality of life improved significantly also during follow-up. In summary, the use of tricalcium phosphate-embedded autologous MSCs with lumbar posterolateral arthrodesis is safe and potentially provides long-term benefits for 10 years.

Long-Term Results of a Phase I/II Clinical Trial of Autologous Mesenchymal Stem Cell Therapy for Femoral Head Osteonecrosis.

(1) Background: Osteonecrosis of the femoral head (ONFH) is characterized by impaired vascularization with ischemia resulting in bone cell death, leading to the deterioration of the hip joint. Mesenchymal stem/stromal cells (MSCs) are an attractive potential therapeutic approach in this setting. The aim of this study is to evaluate the clinical improvement in terms of pain and quality of life, as well as the safety of the procedure during the follow-up of patients. (2) Methods: A Phase I-II Open-Label Non-Randomized Prospective clinical trial was conducted. Eight patients with idiopathic ONFH and stage < IIC in the ARCO classification were included. Four weeks before therapy, 40 mL of autologous bone marrow was obtained, and MSCs were expanded under Good-Manufacturing-Practice (GMP) standards. Study medication consisted of a suspension of autologous BM-derived MSCs (suspended in a solution of 5-10 mL of saline and 5% human albumin) in a single dose of 0.5-1 × 106 cells/kg of the patient, administered intraosseously with a trocar and under radioscopic control. Per-protocol monitoring of patients included a postoperative period of 12 months, with a clinical and radiological assessment that included the visual analog scale (VAS), the Harris scale, the SF-36, and the radiological evolution of both hips. In addition, all patients were further followed up for eight years to assess the need for long-term total hip replacement (THR) surgery. (3) Results: Median age of patients included was 48.38 ± 7.38 years, and all patients were men. Autologous MSCs were expanded in all cases. There were no adverse effects related to cell administration. Regarding efficacy, both VAS and ODI scores improved after surgery. Radiologically, 12.5% of patients improved at the end of follow-up, whereas 50% improved clinically. No adverse effects related to the procedure were recorded, and none of the patients needed THR surgery within the first year after MSC therapy. (4) Conclusions: The use of autologous MSCs for patients with ONFH disease is feasible, safe in the long term, and potentially effective.

Autologous mesenchymal stromal cells embedded in tricalcium phosphate for posterolateral spinal fusion: results of a prospective phase I/II clinical trial with long-term follow-up.

BACKGROUND: Posterolateral spinal fusion with autologous bone graft is considered the "gold standard" for lumbar degenerative disc disease (DDD) when surgical treatment is indicated. The potential role of mesenchymal stromal cells (MSCs) to replace the bone graft in this setting has not been fully addressed. OBJECTIVE: To analyze the safety, feasibility and potential clinical efficacy of the implantation of autologous MSCs embedded with tricalcium phosphate as a therapeutic alternative to bone graft in patients with DDD during posterolateral spine fusion. STUDY DESIGN: Phase I/II single-arm prospective clinical trial. METHODS: Eleven patients with monosegmental DDD at L4-L5 or L5-S1 level were included. Autologous bone marrow-derived MSC were expanded in our Good Manufacturing Practice (GMP) Facility and implanted during spinal surgery embedded in a tricalcium phosphate carrier. Monitoring of patients included a postoperative period of 12 months with four visits (after the 1st, 3rd, 6th, and 12th month), with clinical and radiological assessment that included the visual analog scale (VAS), the Oswestry disability index (ODI), the Short-Form Health Survey (SF-36), the vertebral fusion grade observed through a simple Rx, and the evaluation of possible complications or adverse reactions. In addition, all patients were further followed up to 5 years for outcome. RESULTS: Median age of patients included was 44 years (range 30-58 years), and male/female ratio was (6/5) L4-L5 and L5-S1 DDD was present five and six patients, respectively. Autologous MSCs were expanded in all cases. There were no adverse effects related to cell implantation. Regarding efficacy, both VAS and ODI scores improved after surgery. Radiologically, 80% of patients achieved lumbar fusion at the end of the follow-up. No adverse effects related to the procedure were recorded. CONCLUSIONS: The use of autologous MSCs for spine fusion in patients with monosegmental degenerative disc disease is feasible, safe, and potentially effective. TRIAL REGISTRATION: no. EudraCT: 2010-018335-17 ; code Identifier: NCT01513694 ( clinicaltrials.gov ).

Sequential intravenous allogeneic mesenchymal stromal cells as a potential treatment for thromboangiitis obliterans (Buerger's disease).

Thromboangiitis obliterans (TAO), also known as Buerger's Disease, is an occlusive vasculitis linked with high morbidity and amputation risk. To date, TAO is deemed incurable due to the lack of a definitive treatment. The immune system and inflammation are proposed to play a central role in TAO pathogenesis. Due to their immunomodulatory effects, mesenchymal stromal cells (MSCs) are the subject of intense research for the treatment of a wide range of immune-mediated diseases. Thus far, local intramuscular injections of autologous or allogeneic MSCs have shown promising results in TAO. However, sequential intravenous allogeneic MSC administration has not yet been explored, which we hypothesized could exert a systemic anti-inflammatory effect in the vasculature and modulate the immune response. Here, we report the first case of a TAO patient at amputation risk treated with four sequential intravenous infusions of bone marrow-derived allogeneic MSCs from a healthy donor. Following administration, there was significant regression of foot skin ulcers and improvements in rest pain, Walking Impairment Questionnaire scores, and quality of life. Sixteen months after the infusion, the patient had not required any further amputations. This report highlights the potential of sequential allogeneic MSC infusions as an effective treatment for TAO, warranting further studies to compare this approach with the more conventionally used intramuscular MSC administration and other cell-based therapies.

Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II).

BACKGROUND: Mesenchymal stromal cells are a promising option to treat knee osteoarthritis. Their safety and usefulness must be confirmed and the optimal dose established. We tested increasing doses of bone marrow mesenchymal stromal cells (BM-MSCs) in combination with hyaluronic acid in a randomized clinical trial. MATERIALS: A phase I/II multicenter randomized clinical trial with active control was conducted. Thirty patients diagnosed with knee OA were randomly assigned to intraarticularly administered hyaluronic acid alone (control), or together with 10 × 10(6) or 100 × 10(6) cultured autologous BM-MSCs, and followed up for 12 months. Pain and function were assessed using VAS and WOMAC and by measuring the knee motion range. X-ray and magnetic resonance imaging analyses were performed to analyze joint damage. RESULTS: No adverse effects were reported after BM-MSC administration or during follow-up. BM-MSC-administered patients improved according to VAS during all follow-up evaluations and median value (IQR) for control, low-dose and high-dose groups change from 5 (3, 7), 7 (5, 8) and 6 (4, 8) to 4 (3, 5), 2 (1, 3) and 2 (0,4) respectively at 12 months (low-dose vs control group p = 0.005 and high-dose vs control group p < 0.009). BM-MSC-administered patients were also superior according to WOMAC, although improvement in control and low-dose patients could not be significantly sustained beyond 6 months. On the other hand, the BM-MSC high-dose group exhibited an improvement of 16.5 (12, 19) points at 12 months (p < 0.01). Consistent with WOMAC and VAS values, motion ranges remained unaltered in the control group but improved at 12 months with BM-MSCs. X-ray revealed a reduction of the knee joint space width in the control group that was not seen in BM-MSCs high-dose group. MRI (WORMS protocol) showed that joint damage decreased only in the BM-MSC high-dose group, albeit slightly. CONCLUSIONS: The single intraarticular injection of in vitro expanded autologous BM-MSCs together with HA is a safe and feasible procedure that results in a clinical and functional improvement of knee OA, especially when 100 × 10(6) cells are administered. These results pave the way for a future phase III clinical trial. CLINICAL TRIALS: gov identifier NCT02123368. Nº EudraCT: 2009-017624-72.

Allogeneic mesenchymal stem cell therapy for refractory cytopenias after hematopoietic stem cell transplantation.

BACKGROUND: Posttransplant cytopenias are a severe complication after allogeneic stem cell transplantation (allo-SCT) and their origin is often multifactorial or unknown. They are frequently refractory to standard therapy, which may include steroids and/or immunoglobulins. Mesenchymal stem cells (MSCs) are an attractive therapeutic tool in the allo-SCT setting for the ability to enhance engraftment as well as acting as immunosuppressants for graft-versus-host disease. There is no prior experience in the literature of the use of MSCs to treat cytopenias after allo-SCT. CASE REPORTS: In this work we report for the first time four cases of refractory posttransplant cytopenias (three patients with thrombocytopenia and one with neutropenia) that were treated with MSCs from a third-party donor. MSCs were expanded from 100 mL of marrow obtained under standard good manufacturing practice conditions. Most patients received more than one cell dose, and median dose of MSCs administered was 1 × 10(6) /kg. RESULTS: All patients recovered normal blood counts, with a mean follow-up of 12.5 months. There were no adverse events related to MSC administration. CONCLUSION: MSC therapy may contribute to the recovery of refractory posttransplant peripheral cytopenias in patients undergoing allo-SCT.