Assessing the safety of stem cell therapeutics

by Alexey Bersenev on June 2, 2011 · 0 comments

in cell product, reviews

Post to Twitter Send Gmail Post to LinkedIn

Great analytical review about cell therapy risk assessment have been published today in Cell Stem Cell. If you’re a developer of cell therapeutics, you can’t miss it! Must read!

Risks and safety is the hottest topic in stem cell research and cell therapy today. Right now, we are at the stage of recognition and determining the risks. But we don’t know how to assess it properly. Especially we don’t know how to assess it clinically. The balance between acceptable risk and safety could be very delicate. So, accurate and sophisticated risks assessment is extremely important:

Importantly, the stem cell therapy field needs to interact at the level of therapy provider, safety scientist, and drug regulator in order to define the acceptable risk associated with a particular treatment and to set in place a framework for accurate assessment of that risk. In our increasingly risk-averse society it is easy to err on the side of caution, but it should be acknowledged that if the safety bar is set unreasonably high then the enormous potential and promise of revolutionary medical treatments may never be realized.

The authors highlighted the importance of assays development and validation for stem cell therapy safety assessment. They pointed out that there are some proposed preclinical assays for purity, tumorigenicity and immunogenicity of the graft. It remains unclear which assay will play a significant role in regulatory requirement for stem cell therapies development.
Some excerpts below:

purity check:

Engraftment of undesired, fully differentiated cell types into an ectopic tissue might also have detrimental effects. The purity of the differentiated cells can be fully characterized by evaluating various markers of undifferentiated cells (such as TRA-1-60), markers of the specific cell type of interest, and markers of undesired cell types of the same/other lineages. The evaluation of such markers can be achieved using a quantitative polymerase chain reaction assay (qPCR), flow cytometry, and immunohistochemistry, and a combination of these methods might provide detailed knowledge of the purity of the culture.

mutagenesis and tumorigenicity:

Genetic changes in culture must also be evaluated in order to determine the safety of the therapy. Cells in culture, and stem cells in particular, accumulate chromosomal aberrations, especially at high passage numbers (Baker et al., 2007,Mayshar et al., 2010). These chromosomal abnormalities must be fully characterized and risk assessed before exposure to a patient. Analysis of karyotypic changes at passage numbers corresponding to those found in the product would help to assess safety. Furthermore, where transgenes are used in a product, the possibility of insertional mutagenesis, and therefore a cancer risk, must be studied. In addition, as recent studies have demonstrated that subkaryotypic changes, and even point mutations in coding regions, might arise in stem cell cultures (Gore et al., 2011,Hussein et al., 2011,Laurent et al., 2011), more accurate and expensive methods for the evaluation of the genomic integrity such as array comparative genomic hybridization (aCGH) and single-nucleotide polymorphism array (SNP array) might also be required.

animal tests with longer follow-up:

With regard to animal testing of stem cell products, analysis is limited by the lifespan of the animal, compared with the lifespan of a human patient, and longer follow-up studies are likely to be required for early human stem cell trials as compared to conventional medicines.
Furthermore, testing of the product may be carried out at passage numbers beyond routine use, to ensure the product remains safe, particularly with regards to tumor formation and immunogenicity.

detection and tracking of engrafted cells:

Another potential safety issue is that of migration of cells from the graft. Cells can be tracked using several different methods, such as genetic labeling, immunohistochemistry, and bioluminescence techniques.
However, it becomes more complicated to analyze biodistribution of human cells in a human host. If the cells in the stem cell therapeutic are adequately characterized, the HLA type should be known and the host and graft cells can be discriminated based on immunological characteristics, assuming that imaging technology has sufficient resolution in human subjects.

Finally, the authors proposed to facilitate our efforts on the following areas: models systems, safety and efficacy biomarkers, immunogenicity/ immunotoxicity and tumorigenicity.

In summary, it is not clear whether the state of our understanding is sufficient to appraise the safety of these therapies in a comprehensive manner, and we therefore require further sensitive and robust approaches in bioanalysis to monitor them. At a broader level, it is also important to raise the question of whether we are setting a higher bar for the clinical implementation of stem cell-derived therapeutics than we currently apply for other types of cellular therapy. There is a danger that if perfection is a prerequisite for beginning, then we will never begin.

Full text is available for free until the end of June.

{ 0 comments… add one now }

Leave a Comment

Previous post:

Next post: