title: Pre-clinical safety testing supporting clinical use of allogeneic multipotent adult progenitor cells.
abstract: BACKGROUND
  Successful clinical development of novel cellular therapeutics requires the evaluation of clinical acute toxicity endpoints in scoring patient adverse events (AE) contributing to dose-limiting toxicity (DLT) for establishment of the maximum-tolerated dose (MTD). However, many clinical pathology parameters are not routinely evaluated in pre-clinical safety testing. The objective of this pre-clinical study was to investigate thoroughly the acute toxicity of single- and multiple-dose administrations of allogeneic multipotent adult progenitor cells (MultiStem), which represent a class of stromal stem cells with therapeutic potential.
  
  
  METHODS
  MultiStem were tested as an adjunct treatment in a rat myeloablative hematopoietic stem cell transplantation (HSCT) model for impact on clinical parameters, clinical chemistry, hematology, immunology and histopathology parameters. Animals received MultiStem in a single dose of 12.5 million cells/kg on day 2 after HSCT or in five infusions at this dose on days 2, 9, 16, 23 and 30. Controls received phosphate-buffered saline injections and all animals were killed on day 37.
  
  
  RESULTS
  There were no significant differences between tests and controls regarding evaluation of respiratory distress upon infusion, clinical assessment and hematology and clinical chemistry analysis. Gross necropsy and histopathology analysis showed no organ profile alterations. There was no significant evidence for allogeneic antibody production or T-cell sensitization upon MultiStem infusion.
  
  
  CONCLUSIONS
  These studies demonstrate the safety of administration of allogeneic stromal stem cells in repeat dosing regimens in bone marrow transplant settings, and define pre-clinical safety testing standards relevant to the development of cellular therapeutics using allogeneic adherent adult stem cells.
authors.affiliation: Center for Hematologic Malignancies, OHSU Cancer Institute, Oregon Health and Science University, Portland,Oregon, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kovacsovics-Bankowski
authors.forename: K
authors.initials: K
authors.lastname: Mauch
authors.forename: A
authors.initials: A
authors.lastname: Raber
authors.forename: P R
authors.initials: PR
authors.lastname: Streeter
authors.forename: R J
authors.initials: RJ
authors.lastname: Deans
authors.forename: R T
authors.initials: RT
authors.lastname: Maziarz
authors.forename: W
authors.initials: W
authors.lastname: Van't Hof
mesh_terms: D053687:Adult Stem Cells / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation*; D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology*; D004195:Disease Models, Animal; D039902:Multipotent Stem Cells / Q000276:immunology / Q000637:transplantation*; D051381:Rats; D011915:Rats, Inbred BUF; D014184:Transplantation, Homologous / Q000009:adverse effects / Q000276:immunology