Assessment of CAR-T Cell-Mediated Cytotoxicity in 3D Microfluidic Cancer Co-Culture Models for Combination Therapy
Chimeric antigen receptor (CAR)-T cell therapy is efficacious against many haematological malignancies, but challenges remain when using this cellular immunotherapy for treating solid tumours. Classical 2D <italic>in vitro</italic> models fail to recapitulate the complexity of the tumour...
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| Format: | Article |
| Language: | English |
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IEEE
2022-01-01
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| Series: | IEEE Open Journal of Engineering in Medicine and Biology |
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| Online Access: | https://ieeexplore.ieee.org/document/9783024/ |
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| _version_ | 1849707688294875136 |
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| author | Karla Paterson Sarah Paterson Theresa Mulholland Seth B. Coffelt Michele Zagnoni |
| author_facet | Karla Paterson Sarah Paterson Theresa Mulholland Seth B. Coffelt Michele Zagnoni |
| author_sort | Karla Paterson |
| collection | DOAJ |
| description | Chimeric antigen receptor (CAR)-T cell therapy is efficacious against many haematological malignancies, but challenges remain when using this cellular immunotherapy for treating solid tumours. Classical 2D <italic>in vitro</italic> models fail to recapitulate the complexity of the tumour microenvironment, whilst <italic>in vivo</italic> models, such as patient-derived xenografts, are costly and labour intensive. Microfluidic technologies can provide miniaturized solutions to assess CAR-T therapies in 3D complex preclinical models of solid tumours. Here, we present a novel microfluidic immunoassay for the evaluation of CAR-T cell cytotoxicity and targeting specificity on 3D spheroids containing cancer cells and stromal cells. Monitoring the interaction between CAR-T cells and spheroid co-cultures, we show that CAR-T cells home towards target-expressing cancer cells and elicit a cytotoxic effect. Testing CAR-T cells in combination therapies, we show that CAR-T cell cytotoxicity is enhanced with anti-PD-L1 therapy and carboplatin chemotherapy. We propose this proof-of-concept microfluidic immunoassay as a material-saving, pre-clinical screening tool for quantification of cell therapy efficacy. |
| format | Article |
| id | doaj-art-eaba4ea35d8546e281cfac93783da60e |
| institution | DOAJ |
| issn | 2644-1276 |
| language | English |
| publishDate | 2022-01-01 |
| publisher | IEEE |
| record_format | Article |
| series | IEEE Open Journal of Engineering in Medicine and Biology |
| spelling | doaj-art-eaba4ea35d8546e281cfac93783da60e2025-08-20T03:15:51ZengIEEEIEEE Open Journal of Engineering in Medicine and Biology2644-12762022-01-013869510.1109/OJEMB.2022.31783029783024Assessment of CAR-T Cell-Mediated Cytotoxicity in 3D Microfluidic Cancer Co-Culture Models for Combination TherapyKarla Paterson0https://orcid.org/0000-0002-7632-1308Sarah Paterson1https://orcid.org/0000-0003-3441-5813Theresa Mulholland2https://orcid.org/0000-0002-2837-0519Seth B. Coffelt3https://orcid.org/0000-0003-2257-2862Michele Zagnoni4https://orcid.org/0000-0003-3198-9491Centre for Microsystems and Photonics, EEE Department, University of Strathclyde, Glasgow, U.K.ScreenIn3D Limited, Technology and Innovation Centre, Glasgow, U.K.ScreenIn3D Limited, Technology and Innovation Centre, Glasgow, U.K.Institute of Cancer Sciences, University of Glasgow, Glasgow, U.K.Centre for Microsystems and Photonics, EEE Department, University of Strathclyde, Glasgow, U.K.Chimeric antigen receptor (CAR)-T cell therapy is efficacious against many haematological malignancies, but challenges remain when using this cellular immunotherapy for treating solid tumours. Classical 2D <italic>in vitro</italic> models fail to recapitulate the complexity of the tumour microenvironment, whilst <italic>in vivo</italic> models, such as patient-derived xenografts, are costly and labour intensive. Microfluidic technologies can provide miniaturized solutions to assess CAR-T therapies in 3D complex preclinical models of solid tumours. Here, we present a novel microfluidic immunoassay for the evaluation of CAR-T cell cytotoxicity and targeting specificity on 3D spheroids containing cancer cells and stromal cells. Monitoring the interaction between CAR-T cells and spheroid co-cultures, we show that CAR-T cells home towards target-expressing cancer cells and elicit a cytotoxic effect. Testing CAR-T cells in combination therapies, we show that CAR-T cell cytotoxicity is enhanced with anti-PD-L1 therapy and carboplatin chemotherapy. We propose this proof-of-concept microfluidic immunoassay as a material-saving, pre-clinical screening tool for quantification of cell therapy efficacy.https://ieeexplore.ieee.org/document/9783024/Immunotherapylab-on-a-chipsolid tumour microenvironmentthree-dimensional in vitro complex model |
| spellingShingle | Karla Paterson Sarah Paterson Theresa Mulholland Seth B. Coffelt Michele Zagnoni Assessment of CAR-T Cell-Mediated Cytotoxicity in 3D Microfluidic Cancer Co-Culture Models for Combination Therapy IEEE Open Journal of Engineering in Medicine and Biology Immunotherapy lab-on-a-chip solid tumour microenvironment three-dimensional in vitro complex model |
| title | Assessment of CAR-T Cell-Mediated Cytotoxicity in 3D Microfluidic Cancer Co-Culture Models for Combination Therapy |
| title_full | Assessment of CAR-T Cell-Mediated Cytotoxicity in 3D Microfluidic Cancer Co-Culture Models for Combination Therapy |
| title_fullStr | Assessment of CAR-T Cell-Mediated Cytotoxicity in 3D Microfluidic Cancer Co-Culture Models for Combination Therapy |
| title_full_unstemmed | Assessment of CAR-T Cell-Mediated Cytotoxicity in 3D Microfluidic Cancer Co-Culture Models for Combination Therapy |
| title_short | Assessment of CAR-T Cell-Mediated Cytotoxicity in 3D Microfluidic Cancer Co-Culture Models for Combination Therapy |
| title_sort | assessment of car t cell mediated cytotoxicity in 3d microfluidic cancer co culture models for combination therapy |
| topic | Immunotherapy lab-on-a-chip solid tumour microenvironment three-dimensional in vitro complex model |
| url | https://ieeexplore.ieee.org/document/9783024/ |
| work_keys_str_mv | AT karlapaterson assessmentofcartcellmediatedcytotoxicityin3dmicrofluidiccancercoculturemodelsforcombinationtherapy AT sarahpaterson assessmentofcartcellmediatedcytotoxicityin3dmicrofluidiccancercoculturemodelsforcombinationtherapy AT theresamulholland assessmentofcartcellmediatedcytotoxicityin3dmicrofluidiccancercoculturemodelsforcombinationtherapy AT sethbcoffelt assessmentofcartcellmediatedcytotoxicityin3dmicrofluidiccancercoculturemodelsforcombinationtherapy AT michelezagnoni assessmentofcartcellmediatedcytotoxicityin3dmicrofluidiccancercoculturemodelsforcombinationtherapy |