A Reproducible Bioprinted 3D Tumor Model Serves as a Preselection Tool for CAR T Cell Therapy Optimization
Chimeric antigen receptor (CAR) T cell performance against solid tumors in mouse models and clinical trials is often less effective than predicted by CAR construct selection in two-dimensional (2D) cocultures. Three-dimensional (3D) solid tumor architecture is likely to be crucial for CAR T cell eff...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.689697/full |
| _version_ | 1818936404009287680 |
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| author | Laura Grunewald Laura Grunewald Tobias Lam Tobias Lam Lena Andersch Anika Klaus Silke Schwiebert Annika Winkler Anton Gauert Anja I. Heeren-Hagemann Kathy Astrahantseff Filippos Klironomos Alexander Thomas Alexander Thomas Hedwig E. Deubzer Hedwig E. Deubzer Hedwig E. Deubzer Hedwig E. Deubzer Anton G. Henssen Anton G. Henssen Angelika Eggert Angelika Eggert Angelika Eggert Angelika Eggert Johannes H. Schulte Johannes H. Schulte Johannes H. Schulte Kathleen Anders Kathleen Anders Lutz Kloke Lutz Kloke Annette Künkele Annette Künkele Annette Künkele Annette Künkele |
| author_facet | Laura Grunewald Laura Grunewald Tobias Lam Tobias Lam Lena Andersch Anika Klaus Silke Schwiebert Annika Winkler Anton Gauert Anja I. Heeren-Hagemann Kathy Astrahantseff Filippos Klironomos Alexander Thomas Alexander Thomas Hedwig E. Deubzer Hedwig E. Deubzer Hedwig E. Deubzer Hedwig E. Deubzer Anton G. Henssen Anton G. Henssen Angelika Eggert Angelika Eggert Angelika Eggert Angelika Eggert Johannes H. Schulte Johannes H. Schulte Johannes H. Schulte Kathleen Anders Kathleen Anders Lutz Kloke Lutz Kloke Annette Künkele Annette Künkele Annette Künkele Annette Künkele |
| author_sort | Laura Grunewald |
| collection | DOAJ |
| description | Chimeric antigen receptor (CAR) T cell performance against solid tumors in mouse models and clinical trials is often less effective than predicted by CAR construct selection in two-dimensional (2D) cocultures. Three-dimensional (3D) solid tumor architecture is likely to be crucial for CAR T cell efficacy. We used a three-dimensional (3D) bioprinting approach for large-scale generation of highly reproducible 3D human tumor models for the test case, neuroblastoma, and compared these to 2D cocultures for evaluation of CAR T cells targeting the L1 cell adhesion molecule, L1CAM. CAR T cells infiltrated the model, and both CAR T and tumor cells were viable for long-term experiments and could be isolated as single-cell suspensions for whole-cell assays quantifying CAR T cell activation, effector function and tumor cell cytotoxicity. L1CAM-specific CAR T cell activation by neuroblastoma cells was stronger in the 3D model than in 2D cocultures, but neuroblastoma cell lysis was lower. The bioprinted 3D neuroblastoma model is highly reproducible and allows detection and quantification of CAR T cell tumor infiltration, representing a superior in vitro analysis tool for preclinical CAR T cell characterization likely to better select CAR T cells for in vivo performance than 2D cocultures. |
| first_indexed | 2024-12-20T05:35:31Z |
| format | Article |
| id | doaj.art-36d3f87310c541579111c11eb4745bb7 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-20T05:35:31Z |
| publishDate | 2021-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-36d3f87310c541579111c11eb4745bb72022-12-21T19:51:38ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-06-011210.3389/fimmu.2021.689697689697A Reproducible Bioprinted 3D Tumor Model Serves as a Preselection Tool for CAR T Cell Therapy OptimizationLaura Grunewald0Laura Grunewald1Tobias Lam2Tobias Lam3Lena Andersch4Anika Klaus5Silke Schwiebert6Annika Winkler7Anton Gauert8Anja I. Heeren-Hagemann9Kathy Astrahantseff10Filippos Klironomos11Alexander Thomas12Alexander Thomas13Hedwig E. Deubzer14Hedwig E. Deubzer15Hedwig E. Deubzer16Hedwig E. Deubzer17Anton G. Henssen18Anton G. Henssen19Angelika Eggert20Angelika Eggert21Angelika Eggert22Angelika Eggert23Johannes H. Schulte24Johannes H. Schulte25Johannes H. Schulte26Kathleen Anders27Kathleen Anders28Lutz Kloke29Lutz Kloke30Annette Künkele31Annette Künkele32Annette Künkele33Annette Künkele34Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Oncology and Hematology, Berlin, GermanyFreie Universität Berlin, Berlin, GermanyTechnische Universität Berlin, Berlin, GermanyCellbricks GmbH Berlin, Berlin, GermanyCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Oncology and Hematology, Berlin, GermanyCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Oncology and Hematology, Berlin, GermanyCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Oncology and Hematology, Berlin, GermanyCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Oncology and Hematology, Berlin, GermanyCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Oncology and Hematology, Berlin, GermanyCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Oncology and Hematology, Berlin, GermanyCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Oncology and Hematology, Berlin, GermanyCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Oncology and Hematology, Berlin, GermanyTechnische Universität Berlin, Berlin, GermanyCellbricks GmbH Berlin, Berlin, GermanyCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Oncology and Hematology, Berlin, GermanyNeuroblastoma Research Group, Experimental and Clinical Research Center (ECRC) of the Charité and the Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin, GermanyGerman Cancer Consortium (DKTK), Heidelberg, GermanyGerman Cancer Research Center (DKFZ), Heidelberg, GermanyCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Oncology and Hematology, Berlin, GermanyBerlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, GermanyCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Oncology and Hematology, Berlin, GermanyGerman Cancer Consortium (DKTK), Heidelberg, GermanyGerman Cancer Research Center (DKFZ), Heidelberg, GermanyBerlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, GermanyCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Oncology and Hematology, Berlin, GermanyGerman Cancer Consortium (DKTK), Heidelberg, GermanyGerman Cancer Research Center (DKFZ), Heidelberg, GermanyCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Oncology and Hematology, Berlin, GermanyGerman Cancer Research Center (DKFZ), Heidelberg, GermanyTechnische Universität Berlin, Berlin, GermanyCellbricks GmbH Berlin, Berlin, GermanyCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Oncology and Hematology, Berlin, GermanyGerman Cancer Consortium (DKTK), Heidelberg, GermanyGerman Cancer Research Center (DKFZ), Heidelberg, GermanyBerlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, GermanyChimeric antigen receptor (CAR) T cell performance against solid tumors in mouse models and clinical trials is often less effective than predicted by CAR construct selection in two-dimensional (2D) cocultures. Three-dimensional (3D) solid tumor architecture is likely to be crucial for CAR T cell efficacy. We used a three-dimensional (3D) bioprinting approach for large-scale generation of highly reproducible 3D human tumor models for the test case, neuroblastoma, and compared these to 2D cocultures for evaluation of CAR T cells targeting the L1 cell adhesion molecule, L1CAM. CAR T cells infiltrated the model, and both CAR T and tumor cells were viable for long-term experiments and could be isolated as single-cell suspensions for whole-cell assays quantifying CAR T cell activation, effector function and tumor cell cytotoxicity. L1CAM-specific CAR T cell activation by neuroblastoma cells was stronger in the 3D model than in 2D cocultures, but neuroblastoma cell lysis was lower. The bioprinted 3D neuroblastoma model is highly reproducible and allows detection and quantification of CAR T cell tumor infiltration, representing a superior in vitro analysis tool for preclinical CAR T cell characterization likely to better select CAR T cells for in vivo performance than 2D cocultures.https://www.frontiersin.org/articles/10.3389/fimmu.2021.689697/fullCAR T cellsneuroblastomaT cell infiltration3D tumor modelbioprint technology |
| spellingShingle | Laura Grunewald Laura Grunewald Tobias Lam Tobias Lam Lena Andersch Anika Klaus Silke Schwiebert Annika Winkler Anton Gauert Anja I. Heeren-Hagemann Kathy Astrahantseff Filippos Klironomos Alexander Thomas Alexander Thomas Hedwig E. Deubzer Hedwig E. Deubzer Hedwig E. Deubzer Hedwig E. Deubzer Anton G. Henssen Anton G. Henssen Angelika Eggert Angelika Eggert Angelika Eggert Angelika Eggert Johannes H. Schulte Johannes H. Schulte Johannes H. Schulte Kathleen Anders Kathleen Anders Lutz Kloke Lutz Kloke Annette Künkele Annette Künkele Annette Künkele Annette Künkele A Reproducible Bioprinted 3D Tumor Model Serves as a Preselection Tool for CAR T Cell Therapy Optimization Frontiers in Immunology CAR T cells neuroblastoma T cell infiltration 3D tumor model bioprint technology |
| title | A Reproducible Bioprinted 3D Tumor Model Serves as a Preselection Tool for CAR T Cell Therapy Optimization |
| title_full | A Reproducible Bioprinted 3D Tumor Model Serves as a Preselection Tool for CAR T Cell Therapy Optimization |
| title_fullStr | A Reproducible Bioprinted 3D Tumor Model Serves as a Preselection Tool for CAR T Cell Therapy Optimization |
| title_full_unstemmed | A Reproducible Bioprinted 3D Tumor Model Serves as a Preselection Tool for CAR T Cell Therapy Optimization |
| title_short | A Reproducible Bioprinted 3D Tumor Model Serves as a Preselection Tool for CAR T Cell Therapy Optimization |
| title_sort | reproducible bioprinted 3d tumor model serves as a preselection tool for car t cell therapy optimization |
| topic | CAR T cells neuroblastoma T cell infiltration 3D tumor model bioprint technology |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.689697/full |
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