Pre-clinical safety testing supporting clinical use of allogeneic multipotent adult progenitor cells
M Kovacsovics-Bankowski1, K Mauch, A Raber
1Center for Hematologic Malignancies, OHSU Cancer Institute, Oregon Health and Science University, Portland,Oregon, USA.
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.
Discussion:
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.
Insights
Allogeneic multipotent adult progenitor cells (MultiStem) showed no significant toxicity in a rat hematopoietic stem cell transplantation model. These findings support the safety of MultiStem for cellular therapeutics development.
Area of Science:
- Stem cell therapy
- Pre-clinical safety evaluation
- Cellular therapeutics development
Background:
- Clinical development of novel cellular therapeutics necessitates evaluation of acute toxicity endpoints for dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD).
- Pre-clinical safety testing often omits comprehensive evaluation of clinical pathology parameters.
- Allogeneic multipotent adult progenitor cells (MultiStem), a type of stromal stem cell, have therapeutic potential requiring thorough safety assessment.
Purpose of the Study:
- To investigate the acute toxicity of single and multiple doses of allogeneic multipotent adult progenitor cells (MultiStem).
- To establish pre-clinical safety testing standards for allogeneic adherent adult stem cells in cellular therapeutics.
Main Methods:
- MultiStem was administered as an adjunct treatment in a rat myeloablative hematopoietic stem cell transplantation (HSCT) model.
- Animals received either a single dose (12.5 million cells/kg) or five doses of MultiStem on specific days post-HSCT.
- Comprehensive evaluation included clinical parameters, chemistry, hematology, immunology, and histopathology. Controls received phosphate-buffered saline.
Main Results:
- No significant differences were observed between MultiStem-treated and control groups in respiratory distress, clinical assessment, hematology, or clinical chemistry.
- Gross necropsy and histopathology revealed no organ profile alterations.
- No significant allogeneic antibody production or T-cell sensitization was detected upon MultiStem infusion.
Conclusions:
- Administration of allogeneic stromal stem cells, including MultiStem, is safe in repeat dosing regimens within bone marrow transplant settings.
- These studies define relevant pre-clinical safety testing standards for cellular therapeutics utilizing allogeneic adherent adult stem cells.
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