Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products Proceedings of a Workshop (2019) / Chapter Skim
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2 Sources of Variability Associated with Regenerative Therapies: Lessons from Case Studies
2 Sources of Variability Associated with Regenerative Therapies: Lessons from Case Studies
Pages 9-22
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From page 9... ...
• Moving stem cell therapies forward will require that manu facturing and characterization processes be standardized inde pendent of the sources of the cells (e.g., bone marrow, adipose tissue, umbilical cord)
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From page 10... ...
The field of regenerative engineering is now embracing this variability and working to understand it, he said. CASE STUDY 1: VARIABILITY IN THE USE OF MESENCHYMAL STEM CELLS FOR TREATING CARDIOMYOPATHY The focus of the first case study was the use of culture-expanded cell products in clinical trials, specifically the work that Schulman and her colleagues are carrying out at the Interdisciplinary Stem Cell Institute at the University of Miami using mesenchymal stem cells to treat heart failure.
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From page 11... ...
It is also known that mesenchymal stem cells communicate with other cells through gap junctions, stimulate endogenous stem cell differentiation, and interact with cardiac progenitor cells, Schulman said. Mesenchymal Stem Cell Clinical Trials The results of a series of phase I/II clinical trials and a phase II clinical trial of mesenchymal stem cells for the treatment of heart failure were described by Schulman (see Box 2-1)
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From page 12... ...
. The study demonstrated safety and also indicated that the use of the autologous mesenchymal stem cells led to a greater scar size reduction than either treatment with bone marrow or a placebo (Heldman et al., 2014)
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Umbilical Cord–Derived Mesenchymal Stem Cells Umbilical cord–derived mesenchymal stem cells are isolated from the Wharton's jelly, a gelatinous substance within the umbilical cord. The manufacturing processes for mesenchymal stem cells vary, and in order to move cell therapies forward, the manufacturing and characterization processes need to be standardized regardless of cell source (e.g., bone marrow, umbilical cord, adipose tissue)
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Manufacturing Human Neural Progenitors from Fetal Tissue The method used by Svendsen's laboratory for isolating and expanding fetal-derived cortical neural progenitor cells involves using a unique chopping technique, he explained. This technique maintains cell-to-cell contact and allows for up to 70 population doublings in culture, he said.
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From page 15... ...
Svendsen described an ongoing clinical study using the neural progenitor cells engineered to release GDNF.2 The cells are injected by a neurosurgeon directly into the spinal cord where the motor neurons are dying. An innovative surgical device was developed to facilitate the delivery of the cells to the spinal cord.
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From page 16... ...
The cell therapies under investigation are still in the early stages, he added, and it is important to be very clear about this in the informed consent. Astrocytes derived from fetal neural progenitor cells might be used to treat many other disease targets, including Parkinson's disease, Huntington's disease, retinitis pigmentosa, stroke, and Alzheimer's disease.
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From page 17... ...
The transition to iPSC technology is under way, he said, but he reiterated that it will be important to ensure stability and reduce variability as well as to implement reliable differentiation protocols. CASE STUDY 3: VARIABILITY IN THE DEVELOPMENT OF CAR T CELL THERAPY The Center for Cellular Engineering is a core processing laboratory at the NIH Clinical Center.
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There was wide variation in the cell counts from the first 28 CD19CAR T cell products manufactured in the core processing laboratory,
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Enrichment and elutriation were less suitable for the manufacture of CD22-CAR T cell products, Stroncek said. Instead, PBMC concentrates were enriched for T cells using CD4 and CD8 monoclonal antibodies conjugated to magnetic beads and a commercial GMP cell separation system (Miltenyi CliniMACS® Plus)
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From page 20... ...
He suggested that using cells from a single donor in a trial could help answer some of the questions of variability as all of the patients would receive the same product. A grant application to study the lot-to-lot variability of mesenchymal stem cells is being developed by Schulman and her colleagues.
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From page 21... ...
Potency will also be variable across batches of product, Svendsen said, and it is not known what impact that differences in genetic sequence might have in terms of patient outcome. High-throughput analysis of the transcriptome has been very helpful, Stroncek said, adding that mesenchymal stem cells made in different laboratories with slightly different techniques have been shown to have highly variable transcriptomes.
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