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Updated: Aug 29, 2025
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
Tumorigenicity Assessment of Human Cancer Cell Lines Xenografted on Immunodeficient Mice as Positive Controls of
Seunghee Oh1, Eun-Young Gu1, Ji-Seok Han1
1Department of Advanced Toxicology Research, 443298Korea Institute of Toxicology, Daejeon, Republic of Korea.
Abstract:
Recent advances in human pluripotent stem cell (hPSC)-derived cell therapies and genome editing technologies such as CRISPR/Cas9 make regenerative medicines promising for curing diseases previously thought to be incurable. However, the possibility of off-target effects during genome editing and the nature of hPSCs, which can differentiate into any cell type and infinitely proliferate, inevitably raises concerns about tumorigenicity. Tumorigenicity acts as a major obstacle to the application of hPSC-derived and gene therapy products in clinical practice. Thus, regulatory authorities demand mandatory tumorigenicity testing as a key pre-clinical safety step for the products. In the tumorigenicity testing, regulatory guidelines request to include human cancer cell line injected positive control group (PC) animals, which must form tumors. As the validity of the whole test is determined by the tumor-forming rates (typically above 90%) of PC animals, establishing the stable tumorigenic condition of PC animals is critical for successful testing. We conducted several studies to establish the proper positive control conditions, including dose, administration routes, and the selection of cell lines, in compliance with Good Laboratory Practice (GLP) regulations and/or guidelines, which are essential for pre-clinical safety tests of therapeutic materials. We expect that our findings provide insights and practical information to create a successful tumorigenicity test and its guidelines.
Insights
Establishing reliable positive controls is crucial for the safety testing of regenerative medicines. This study optimizes conditions for human pluripotent stem cell (hPSC) therapies to ensure accurate tumorigenicity assessments.
Area of Science:
- Regenerative Medicine
- Stem Cell Therapy
- Genome Editing Safety
Background:
- Human pluripotent stem cell (hPSC) therapies and genome editing offer promise for incurable diseases.
- Tumorigenicity of hPSC-derived products is a significant clinical application barrier.
- Regulatory agencies mandate tumorigenicity testing as a critical pre-clinical safety evaluation.
Purpose of the Study:
- To establish optimal positive control conditions for mandatory tumorigenicity testing of regenerative medicine products.
- To ensure the reliability and validity of pre-clinical safety assessments for hPSC-derived therapies and gene editing products.
Main Methods:
- Conducted multiple studies to determine ideal positive control parameters.
- Investigated optimal cell line selection, dosage, and administration routes for positive control groups.
- Ensured all experimental conditions adhered to Good Laboratory Practice (GLP) regulations.
Main Results:
- Identified critical factors for establishing stable tumorigenic conditions in positive control animals.
- Provided practical insights into optimizing the selection and administration of positive control cell lines.
- Validated experimental approaches for ensuring high tumor formation rates (above 90%) in positive control groups.
Conclusions:
- Optimized positive control conditions are essential for the successful and valid execution of tumorigenicity tests.
- Findings offer practical guidance for regulatory compliance and the advancement of hPSC-derived regenerative therapies.
- Standardized positive control strategies will enhance the safety and clinical translation of gene therapy products.
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