Abstract
Human Pluripotent Stem Cell (PSC)-derived cell therapy holds enormous promise because of the cells’ “unlimited” proliferative capacity and the potential to differentiate into any type of cell. However, these features of PSC-derived cell products are associated with concerns regarding the generation of iatrogenic teratomas or tumors from residual immature or non-terminally differentiated cells in the final cell product. This concern has become a major hurdle to the introduction of this therapy into the clinic. Tumorigenicity testing is therefore a key preclinical safety test in PSC-derived cell therapy. Tumorigenicity testing becomes particularly important when autologous human induced Pluripotent Stem Cell (iPSC)-derived cell products with no immuno-barrier are considered for transplantation. There has been, however, no internationally recognized guideline for tumorigenicity testing of PSC-derived cell products for cell therapy. In this review, we outline the points to be considered in the design and execution of tumorigenicity tests, referring to the tests and laboratory work that we have conducted for an iPSC-derived retinal pigment epithelium (RPE) cell product prior to its clinical use.
Highlights
Several notable clinical trials using human Pluripotent Stem Cell (PSC)-derived cell products have been conducted recently
Advanced Cell Technology initiated a study in which embryonic stem cell (ESC)-derived retinal pigment epithelium (RPE) was used for treatment of Stargardt’s disease and dry type Age-related Macular Degeneration (AMD) [2]
The report stated that when tumorigenicity testing of ESC-derived cellular products is undertaken, the tumorigenicity tests should be designed considering the nature of cell products to be transplanted and the anatomical location or microenvironment of the host animal
Summary
Several notable clinical trials using human Pluripotent Stem Cell (PSC)-derived cell products have been conducted recently. Tumorigenicity tests that can assess the tumor-forming potential of transplanted cells are important in the case of PSC-based cell therapies. It is important to assess the potential for differentiation resistance due to incomplete reprogramming or a differentiation bias due to epigenetic memory when iPSC-based therapy is considered In this context, it is necessary to assess the tumor-forming potential of non-terminally differentiated cells as well. To trace the behavior of transplanted cells and their biodistribution over time requires labeling test cells by introducing marker genes by retrovirus or lentivirus that can emit a signal with a high S/N ratio.
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