Single and Multiple Dose MultiStem (Multipotent Adult Progenitor Cell) Therapy Prophylaxis of Acute Graft-versus-Host Disease in Myeloablative Allogeneic Hematopoietic Cell Transplantation: A Phase 1 Trial

Abstract

We conducted a multicenter, phase 1 dose escalation study evaluating the safety of the allogeneic multipotent adult progenitor cell (MAPC, MultiStem, Athersys, Inc., Cleveland, OH) stromal product administered as an adjunct therapy to 36 patients after myeloablative allogeneic hematopoietic cell transplantation (HCT). Patients received increasing doses of MAPC (1, 5, or 10 million cells per kilogram recipient weight) as a single i.v. dose on day +2 after HCT (n = 18), or once weekly for up to 5 doses (1 or 5 million cells per kilogram; n = 18). Infusional and regimen-related toxicities were assessed for 30 days after the last MAPC dose. Of 36 allogeneic HCT donors (17 related and 19 unrelated), 35 were 6/6 HLA matched. MAPC infusions were well tolerated without associated infusional toxicity, graft failure, or increased incidence of infection. Median times to neutrophil (n = 36) and platelet (n = 31) engraftment were 15 (range, 11 to 25) and 16 (range, 11 to 41) days, respectively. The overall cumulative incidences of grades II to IV and III and IV acute graft-versus-host disease (GVHD) at day 100 were 37% and 14%, respectively (n = 36). In the group that received the highest single MAPC dose (10 million cells/kg), day 100 incidence of grade II to IV GVHD was 11.1% (1 of 9) with no observed cases of grade III and IV GVHD. We found no evidence for MHC class II allogeneic antibody induction, although some patients showed an increase in serum anticlass I titers compared with baseline. MAPC contribution to blood chimerism was negligible. These phase I data support the safety of stromal stem cell therapy and suggest that MAPC should be tested prospectively as a novel therapeutic option for GVHD prophylaxis after HCT.

Stem Cell Therapies in Clinical Trials: Progress and Challenges

“…While clinical benefits were shown to be very minor and not of clinical value when MSCs were co-administered in haploidentical hematopoietic stem cell transplants for leukemia (Maziarz et al, 2015), the Athersys Multistem MSCs have shown some apparent benefit in reducing GVHD when used as adjunct therapy for myloablative allogeneic bone marrow cell transplants (Liu et al, 2011). However, purification of hematopoietic stem cells and, in particular, the removal of alloreactive T cells can probably accomplish this even more effectively (Logan et al, 2012;Shizuru et al, 1996).…”

Multipotent adult progenitor cells improve the hematopoietic function in myelodysplasia

“…Because of the potent immunomodulatory and anti-inflammatory effects of MAPC cells and their capacity to enhance hematopoietic recovery following transplantation [16], we hypothesized that MAPC cells could be used as a novel therapy in MDS patients to decrease cytopenias because they might secrete factors that enhance hematopoiesis, reduce inflammation and/or replace defective niche cells.…”

N‐acetylcysteine prevents oxidized low‐density lipoprotein‐induced reduction of MG53 and enhances MG53 protective effect on bone marrow stem cells

“…These cells have extensive replication potential, are commercially available at clinical grade (Athersys Inc, Cleveland, Ohio) and are non‐immunogenic for alloreactive cytotoxic T lymphocyte induction, thus without potential adverse immune reactions . MAPCs have been approved for clinical studies in human patients with multiple disease indications including neurological, cardiovascular and inflammatory and immune diseases in the United States and Europe . Clinical‐grade human MAPCs are safe in human patients and effective on controlling human autoimmune disease and allograft rejection .…”