Phase I Study of Cord Blood Transplantation with Intra-Bone Marrow Injection of Mesenchymal Stem Cells

Background: Delayed hematological recovery, graft failure, and acute graft-versus-host disease (GVHD) remain major problems in cord blood transplantation (CBT). Mesenchymal stem cells (MSCs) are known to support bone marrow (BM) stroma and promote hematopoiesis. Additionally, MSCs possess immunomodulatory properties and are used clinically for the treatment of acute GVHD. Therefore, the use of MSCs to enhance engraftment and prevent GVHD after allogeneic hematopoietic cell transplantation has been explored. Recent clinical trials have shown the safety and feasibility of CBT with intravenous co-transplantation of MSCs in pediatric patients (pts), but not in adults, who are at greater risk of graft failure. Previous preclinical study showed that direct intra-BM injection of MSCs enhanced the engraftment of CB cells more than intravenous injection. Based on these backgrounds, to develop a new strategy not only to enhance engraftment but also to prevent GVHD, we designed a first phase I clinical trial to evaluate the safety of CBT combined with intra-BM injection of MSCs (MSC-CBT) for adults (UMIN-CTR, number 000024291). Methods: This study was a single arm, non-randomized, open-label, single-center, phase I trial. Adult pts with hematological disorders were eligible for this study. The target sample size was 5. MSCs were expanded from BM mononuclear cells harvested from healthy adult donors who were patient's spouse or relative within the fourth degree of relationship. The target dose of MSCs infused was 0.5×106 cells/kg of patient body weight. On the day of CBT, MSCs were injected into the intra-BM of the patient 4 hours before the infusion of a single CB unit. The conditioning regimen varied according to patient characteristics. GVHD prophylaxis was tacrolimus and methotrexate. The primary endpoint of this study was toxicity related to intra-BM injection of MSCs within 14 days after transplantation. Hematopoietic recoveries, clinical outcomes, lymphocyte subsets, and cytokine/chemokine levels were compared with controls (n=6) who received CBT without MSC during same time period in our institute. Results: Between February 2017 and June 2018, 6 pts were enrolled, but one did not meet the criteria for release of MSCs due to insufficient cell counts. Among 5 eligible pts, the median age was 47 years (range, 24-70 years). Four pts (80%) were male. Two pts (40%) had AML in 1st or 2nd CR, 2 (40%) had MDS-EB-2, and one (20%) had malignant lymphoma in 1st remission.