Tumorigenicity assessment of cell therapy products: The need for global consensus and points to consider

Abstract

Pluripotent stem cells offer the potential for an unlimited source for cell therapy products. However, there is concern regarding the tumorigenicity of these products in humans, mainly due to the possible unintended contamination of undifferentiated cells or transformed cells. Because of the complex nature of these new therapies and the lack of a globally accepted consensus on the strategy for tumorigenicity evaluation, a case-by-case approach is recommended for the risk assessment of each cell therapy product. In general, therapeutic products need to be qualified using available technologies, which ideally should be fully validated. In such circumstances, the developers of cell therapy products may have conducted various tumorigenicity tests and consulted with regulators in respective countries. Here, we critically review currently available in vivo and in vitro testing methods for tumorigenicity evaluation against expectations in international regulatory guidelines. We discuss the value of those approaches, in particular the limitations of in vivo methods, and comment on challenges and future directions. In addition, we note the need for an internationally harmonized procedure for tumorigenicity assessment of cell therapy products from both regulatory and technological perspectives.

Impact of Sustained Transforming Growth Factor-β Receptor Inhibition on Chromatin Accessibility and Gene Expression in Cultured Human Endometrial MSC

“…We will also assess the effect of A83-01 withdrawal and reversibility on global chromatin architectural changes and gene expression, and the effect on cryopreservation and thawing. Functional in vivo assays of sustained A83-01-treated eMSC will be assessed using our xenograft mouse model ( Gurung et al, 2018a ) and in tumorigenicity animal models ( Sato et al, 2019 ). In vitro potency assays that reflect in vivo eMSC function need to be developed, based on their angiogenic and immunomodulatory properties.…”

Neural Transplants From Human Induced Pluripotent Stem Cells Rescue the Pathology and Behavioral Defects in a Rodent Model of Huntington’s Disease

“…The potential risk of tumorigenicity cannot be fully excluded in the present study, although no indication of tumor formation was observed in the analysis. Therefore, long-term follow-up studies and various types of evaluations based on global consensus will be useful to address in the future the possibility of tumorigenicity of transplanted NPCs (Lee et al, 2013;Sato et al, 2019).…”

Cell Therapy With Human ESC-Derived Cardiac Cells: Clinical Perspectives

“…Despite the utility of these in vitro tests, tumorigenicity studies in animals still represent a major pillar of the preclinical safety assessment. Several factors have then to be taken into consideration, which include the number of cells to be inoculated, the duration of follow-up, the site of transplantation and the limit of detection of the relevant assays (Sato et al, 2019). The choice of the animal model is particularly critical, keeping in mind that most studies entail transplanting human cells into rodents and, as such, should be interpreted cautiously since xenotransplantation is less likely to induce teratomas than allografts (Erdö et al, 2003).…”