Assessment of CAR-T mediated and targeted cytotoxicity in 3D microfluidic TBNC co-culture models for combination therapy

Paterson, K., Paterson, S., Mulholland, T., Coffelt, S.B. and Zagnoni, M. (2022) Assessment of CAR-T mediated and targeted cytotoxicity in 3D microfluidic TBNC co-culture models for combination therapy. IEEE Open Journal of Engineering in Medicine and Biology, 3, pp. 86-95. (doi: 10.1109/OJEMB.2022.3178302) (PMID:35813488) (PMCID:PMC9252335)

Abstract

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 in vitro models fail to recapitulate the complexity of the tumour microenvironment, whilst in vivo models, such as patient-derived xenografts, are costly and labour intensive. Microfluidic technologies can provide miniaturised 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.

• Item Type: Articles
• Additional Information: This work was funded by AMS Biotechnology Europe Ltd (industrial PhD studentship to K.P and M.Z) and internal funds by Strathclyde University to M.Z. and K.P.
• Keywords: 3D microfluidic tumor microenvironment, CAR-T, combination therapy, preclinical assays.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Coffelt, Professor Seth
• Authors: Paterson, K., Paterson, S., Mulholland, T., Coffelt, S.B., and Zagnoni, M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: IEEE Open Journal of Engineering in Medicine and Biology
• Publisher: IEEE
• ISSN: 2644-1276
• ISSN (Online): 2644-1276
• Published Online: 27 May 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in IEEE Open Journal of Engineering in Medicine and Biology 3:86-95
• Publisher Policy: Reproduced under a Creative Commons licence