Designing tumorigenicity tests for pluripotent stem cell (PSC)-derived cell products

Although human Pluripotent Stem Cell (PSC)-derived cell therapy shows enormous promise, the tumor-forming potential of PSC-derived cell products should be examined thoroughly. These studies are necessary because of the possible occurrence of tumors originating from residual PSCs in the final product and the genetic instability of PSC-derived cells that may increase in the course of cell culture. For these concerns, a series of pilot studies shall be conducted not to underestimate the risk of tumorigenic events prior to clinical testing. Based on our experience with tumorigenicity testing of iPSC-derived retina pigment epithelial cells and neural stem cells, we propose that the following approaches shall be considered and documented in designing tumorigenicity tests. 1) Detailed quality control records will be maintained for test cells, including gene expression, genetic testing, passage number and growth rate. 2) The type of animal model used and the route and method of administration. 3) Gender, age and the number of animals used for statistical studies. 4) Information about the microenvironment at the transplantation site. 5) The dose of cells to be transplanted with an accompanying justification. 6) Selection of positive control cells and the definition of a positive tumor-forming event. 7) Period of monitoring with an accompanying rationale. 8) Immuno-histochemical (IHC) methods to detect live and human transplanted cells in host tissue. 9) Methods for the detection of ectopic tumors, if any. Among those requirements, the genetic analysis of the PSC-derived cell product is particularly important, as it directly influences the outcome of long-term transplantation tests. Of course, humans have innate genetic variations that may not lead to the development of tumors. In this context, the whole genome sequence or an oncogenic gene panel may not always be useful to predict future tumor formation. Rather, histological analysis of transplants as a part of tumorigenicity testing will provide a phenotypic outcome in the setting of genetic variations or abnormalities. This approach will provide insights to determine which genetic test is relevant to assure the quality of the cell product and consequently increase the reliability of tumorigenicity test results.

کلیدواژه ها:

Design of tumorigenicity tests ، Pluripotent Stem Cell ، iPSC-derived retina pigment epithelium cells ، Whole genome sequence ، Genetic testing