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From spheroids to organoids: next-generation models for CAR-T cell therapy research in solid tumors
Mégane Jassin1, Alix Block1,2, Laury Désiront1
1Laboratory of Hematology, Interdisciplinary Cluster for Applied Genoproteomics Institute (GIGA) Institute, University of Liege, Liege, Belgium.
Frontiers in Immunology
|July 28, 2025
Summary
Three-dimensional (3D) culture models, like spheroids and organoids, are crucial for studying Chimeric Antigen Receptor T-cell (CAR-T) therapy in solid tumors. These advanced models better replicate the tumor microenvironment than traditional 2D methods.
Area of Science:
- Immunotherapy
- Cellular Biology
- Oncology
Background:
- Chimeric Antigen Receptor T-cell (CAR-T) therapy has revolutionized cancer treatment, particularly for hematological malignancies.
- Advancements in CAR-T generations and manufacturing techniques have improved efficacy and persistence.
- Solid tumors present unique challenges for CAR-T therapy, largely due to the limitations of traditional 2D culture systems in replicating the complex tumor microenvironment (TME).
Purpose of the Study:
- To explore the potential of three-dimensional (3D) culture models for studying CAR-T cells in solid tumors.
- To compare the advantages and limitations of 2D versus 3D models in mimicking the TME and CAR-T interactions.
- To review methods for generating 3D models and the role of murine models in preclinical CAR-T research.
Main Methods:
- Review of existing literature on CAR-T therapy, 2D and 3D culture systems, and murine models.
- Discussion of spheroid and organoid generation techniques: direct aggregation, scaffold-based, microfluidic, organs-on-chip, bioprinting, and patient-derived organotypic tumors.
- Analysis of CAR-T cell dynamics, efficacy, and off-target effects in preclinical murine models.
Main Results:
- 3D culture models (spheroids, organoids) offer a more physiologically relevant environment than 2D models for studying CAR-T cells against solid tumors.
- 3D systems better replicate the TME, tumor heterogeneity, and immune interactions crucial for CAR-T efficacy.
- Murine models are valuable for assessing CAR-T cell trafficking, efficacy, and safety in vivo.
Conclusions:
- While 2D models have value, 3D culture systems are essential for accurately studying CAR-T therapy in solid tumors.
- Combining 3D models with murine studies is critical for predicting clinical outcomes.
- Continued development of 3D culture systems is vital for overcoming challenges in solid tumor CAR-T therapy.
