Phase I clinical trial of intra-bone marrow cotransplantation of mesenchymal stem cells in cord blood transplantation

Abstract

Mesenchymal stem cells (MSCs) have immunomodulatory properties and support hematopoiesis in the bone marrow (BM). To develop a new strategy to not only prevent graft-vs-host disease (GVHD) but also to enhance engraftment, a phase I trial of cord blood transplantation (CBT) combined with intra-BM injection of MSCs (MSC-CBT) was designed. Third-party BM-derived MSCs were injected intra-BM on the day of CBT. The conditioning regimen varied according to patient characteristics. GVHD prophylaxis was tacrolimus and methotrexate. The primary endpoint was toxicity related to intra-BM injection of MSCs. Clinical outcomes were compared with those of six controls who received CBT alone. Five adult patients received MSC-CBT, and no adverse events related to intra-BM injection of MSCs were observed. All patients achieved neutrophil, reticulocyte, and platelet recoveries, with median times to recoveries of 21, 35, and 38 days, respectively, comparable with controls. Grade II-IV acute GVHD developed in three controls but not in MSC-CBT patients. No patients developed chronic GVHD in both groups. At 1 year after transplantation, all MSC-CBT patients survived without relapse. This study shows the safety of MSC-CBT, and the findings also suggest that cotransplantation of MSCs may prevent GVHD with no inhibition of engraftment.

Long-Term Biodistribution and Safety of Human Dystrophin Expressing Chimeric Cell Therapy After Systemic-Intraosseous Administration to Duchenne Muscular Dystrophy Model

“…Moreover, the lack of HLA-ABC marker in the non-target organs of blood, bone marrow, liver, lungs, and spleen confirmed safety of intraosseous DEC administration by the lack of evidence of DEC cell migration and lodging in the lungs. This supports the benefits of the intraosseous when compared to intravenous administration of cell-based therapies (Goto et al 2018(Goto et al , 2021Lee et al 2013;Marktel et al 2019;Siemionow et al 2005) where the "first-pass" accumulation of cells in the lungs was reported for MSC delivered via intravenous route (Krueger et al 2018).…”

Long-Term Protective Effect of Human Dystrophin Expressing Chimeric (DEC) Cell Therapy on Amelioration of Function of Cardiac, Respiratory and Skeletal Muscles in Duchenne Muscular Dystrophy

“…Similar findings of higher engraftment rate and amelioration of multi-organ function were confirmed by other investigators following intraosseous administration of bone marrow, cord-blood cells and MSC tested in clinical trials and treatment of blood disorders in both, the adult and pediatric patients’ population [ 72 – 76 ]. Recent Phase I clinical trial confirmed better efficacy of engraftment and safety after intra-bone co-administration of cord blood cells and MSC [ 77 ].…”

Allogeneic stem cell transplantation in the treatment of acute myeloid leukemia: An overview of obstacles and opportunities

“…In recent years, researchers have paid more attention to alternative routes of stem cell administration to reduce the ineffective homing of donor cells[ 55 , 56 ]. Animal model studies have highlighted that compared with intravenous infusion, intra-bone marrow injections for HSPC transplantation are more effective in promoting hematopoietic reconstitution and reducing the incidence of GVHD[ 57 - 59 ]. At present, the clinical application of intra-bone marrow injections is still in its infancy and is mostly used for umbilical cord blood cell transplantation.…”