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Updated: Sep 14, 2025
Hydrogel Arrays Enable Increased Throughput for Screening Effects of Matrix Components and Therapeutics in 3D Tumor Models
Published on: June 16, 2022
Microphysiological Solid Tumor Models in Hydrogel Beads for CAR T Cell Immunotherapy Evaluation
Xuan Peng1,2, Željko Janićijević1, Liliana R Loureiro1
1Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328, Dresden, Germany.
Abstract:
Micrometastases are challenging to resect surgically and to detect with in vivo imaging. Immunotherapy is highly anticipated to revolutionize their treatment, but its overall efficacy still remains limited for solid tumors. Here, a 3D micrometastases model is developed to mimic key microenvironmental cues, enabling in vitro evaluation of chimeric antigen receptor (CAR) T cell immunotherapy. Prostate cancer that preferentially metastasizes to, e.g., liver or bone marrow, is utilized as a model. Hydrogel beads with an elastic modulus matching those of soft organs are used to support long-term culturing, immunostaining, and monitoring of the spheroids. As a biochemical cue, the impact of fibroblast activation protein (FAP), an emerging target in the tumor microenvironment, is investigated on prostate cancer spheroids and on the efficacy of CAR T cell therapy. The multi-spheroid model consists of prostate stem cell antigen (PSCA)-expressing prostate cancer cells and FAP-producing fibrosarcoma cells in varying ratios. The morphological features of the model are compared to clinical histopathology and metastatic murine model samples. Finally, CAR T cell trials demonstrate successful chemoattraction and infiltration through the hydrogel matrix, with a dual-targeting approach against FAP and PSCA antigens showing synergistic efficacy. This research provides invaluable insights for engineering 3D tumor models and modeling therapies targeting small metastatic or residual tumors, suggesting that co-targeting may be a more effective strategy to unlock the tumor microenvironment's suppression.
Insights
A novel 3D micrometastasis model aids in evaluating chimeric antigen receptor (CAR) T cell immunotherapy for solid tumors. Dual targeting of fibroblast activation protein (FAP) and prostate stem cell antigen (PSCA) shows synergistic efficacy against prostate cancer micrometastases.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Immunotherapy
Background:
- Micrometastases pose challenges for surgical resection and in vivo imaging.
- Immunotherapy efficacy for solid tumors remains limited.
- The tumor microenvironment significantly impacts treatment outcomes.
Purpose of the Study:
- To develop a 3D micrometastasis model for in vitro evaluation of CAR T cell immunotherapy.
- To investigate the role of fibroblast activation protein (FAP) in prostate cancer micrometastases and CAR T cell therapy.
- To assess the efficacy of a dual-targeting strategy against FAP and PSCA.
Main Methods:
- A 3D hydrogel bead-based micrometastasis model was created using prostate cancer cells and FAP-producing fibrosarcoma cells.
- The model mimicked soft organ elasticity and incorporated FAP as a biochemical cue.
- Chimeric antigen receptor (CAR) T cell therapy was evaluated in vitro, including a dual-targeting approach.
Main Results:
- The 3D model successfully replicated key microenvironmental cues and morphological features of clinical samples.
- CAR T cells demonstrated chemoattraction and infiltration within the hydrogel matrix.
- Dual targeting of FAP and PSCA antigens exhibited synergistic efficacy, overcoming tumor microenvironment suppression.
Conclusions:
- The developed 3D micrometastasis model is valuable for engineering and evaluating therapies against small metastatic or residual tumors.
- Co-targeting FAP and PSCA antigens represents a promising synergistic strategy for enhancing immunotherapy efficacy.
- This research offers insights into overcoming tumor microenvironment-mediated resistance in cancer treatment.
