TY  - JOUR
AU  - Zhang, Yizheng
AU  - Foth, Ivan
AU  - Makky, Ahmad
AU  - Bucher, Philip
AU  - Grimm, Melanie
AU  - Bruch, Peter-Martin
AU  - Hagelstein, Ilona
AU  - Dietrich, Sascha
AU  - Leibold, Josef
AU  - Flatz, Lukas
AU  - Feucht, Judith
AU  - Becker, Sven
AU  - Schürch, Christian M
TI  - Modeling immunotherapies in live 3D human cancer tissue bioreactors.
JO  - Theranostics
VL  - 16
IS  - 8
SN  - 1838-7640
CY  - Wyoming, NSW
PB  - Ivyspring
M1  - DKFZ-2026-00371
SP  - 3928 - 3945
PY  - 2026
N1  - #DKTKZFB26#
AB  - Background: Cancer immunotherapies have shown remarkable efficacy in advanced malignancies, yet many patients remain unresponsive. This variability, along with concerns about adverse effects and healthcare costs, highlights the need for predictive biomarkers and physiologically relevant cancer models to forecast individual treatment responses. Existing systems inadequately recapitulate the human tumor microenvironment (TME), which is essential for understanding immune-tumor interactions and treatment efficacy. Here, we developed an ex vivo 3D human tissue culture model that preserves the native TME for functional immunotherapy testing. Such a short-term culture platform also supports functional precision medicine by enabling rapid ex vivo assessment of therapeutic responses to guide clinical decisions. Methods: Fresh, intact human lymph node (LN) tissue pieces were cultured in optimized perfusion bioreactors for three days, during which CAR T cell therapies and antibody-based treatments were administered. Post-culture analyses were performed using flow cytometry, histology, and multiplexed fluorescence microscopy. Results: The bioreactor system significantly improved tissue viability compared to traditional plate cultures. Novel CAR T cells with enhanced PI3K signaling exhibited superior tissue infiltration but showed comparable cytotoxicity to conventional CAR T cells. Pembrolizumab, a PD-1 inhibitor, significantly reduced lymphoma and melanoma cell viability without affecting benign LN tissues. Conclusions: This optimized bioreactor culture system provides a robust platform for evaluating immunotherapy efficacy within a physiologically relevant TME. It offers valuable potential for advancing personalized treatment strategies, accelerating the understanding of immunotherapy mechanisms, and improving clinical outcomes.
KW  - Humans
KW  - Bioreactors
KW  - Tumor Microenvironment: immunology
KW  - Immunotherapy, Adoptive: methods
KW  - Neoplasms: therapy
KW  - Neoplasms: immunology
KW  - Neoplasms: pathology
KW  - Lymph Nodes: immunology
KW  - Lymph Nodes: pathology
KW  - Immunotherapy: methods
KW  - Cell Line, Tumor
KW  - Receptors, Chimeric Antigen: immunology
KW  - Tissue Culture Techniques: methods
KW  - 3D tissue culture (Other)
KW  - CAR T cells (Other)
KW  - CODEX multiplexed fluorescence microscopy. (Other)
KW  - immune checkpoint inhibitor (Other)
KW  - perfusion bioreactor (Other)
KW  - Receptors, Chimeric Antigen (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41695488
C2  - pmc:PMC12905668
DO  - DOI:10.7150/thno.118298
UR  - https://inrepo02.dkfz.de/record/309887
ER  -