title: 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.
authors.affiliation: Knight Cancer Institute, Center for Hematologic Malignancies, Oregon Health and Science University, Portland, Oregon. Electronic address: maziarzr@ohsu.edu.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Maziarz
authors.affiliation: Department of Microbiology & Immunology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Timothy
authors.initials: T
authors.lastname: Devos
authors.affiliation: Adult Blood & Marrow Stem Cell Transplant Program, Texas Transplant Institute, San Antonio, Texas.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Bachier
authors.affiliation: University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Goldstein
authors.affiliation: Internal Medicine, Bone Marrow Transplant Program, Mayo Clinic Hospital, Phoenix, Arizona.
authors.forename: Jose F
authors.initials: JF
authors.lastname: Leis
authors.affiliation: Internal Medicine, Bone Marrow Transplant Program, Ohio State University, Columbus, Ohio.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Devine
authors.affiliation: Knight Cancer Institute, Center for Hematologic Malignancies, Oregon Health and Science University, Portland, Oregon.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Meyers
authors.affiliation: Knight Cancer Institute, Center for Hematologic Malignancies, Oregon Health and Science University, Portland, Oregon.
authors.forename: James L
authors.initials: JL
authors.lastname: Gajewski
authors.affiliation: Department of Microbiology & Immunology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Maertens
authors.affiliation: Athersys, Inc., Cleveland, Ohio.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Deans
authors.affiliation: Athersys, Inc., Cleveland, Ohio.
authors.forename: Wouter
authors.initials: W
authors.lastname: Van't Hof
authors.affiliation: University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Hillard M
authors.initials: HM
authors.lastname: Lazarus
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D053687:Adult Stem Cells / Q000637:transplantation*; D000368:Aged; D064591:Allografts; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000517:prevention & control*; D019337:Hematologic Neoplasms / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D039902:Multipotent Stem Cells / Q000637:transplantation*
keywords: Graft-versus-host disease; Mesenchymal stromal cells; Multipotent adult progenitor cells; Myeloablative allogeneic hematopoietic cell transplantation; Phase 1