Paterson Karla, Paterson Sarah, Mulholland Theresa, Coffelt Seth B, Zagnoni Michele
Centre for Microsystems and Photonics, EEE DepartmentUniversity of Strathclyde G1 1XQ Glasgow U.K.
ScreenIn3D LimitedTechnology and Innovation Centre G1 1RD Glasgow U.K.
IEEE Open J Eng Med Biol. 2022 May 27;3:86-95. doi: 10.1109/OJEMB.2022.3178302. eCollection 2022.
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 models fail to recapitulate the complexity of the tumour microenvironment, whilst 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.
嵌合抗原受体（CAR）-T细胞疗法对许多血液系统恶性肿瘤有效，但在使用这种细胞免疫疗法治疗实体瘤时仍存在挑战。传统的二维模型无法重现肿瘤微环境的复杂性，而诸如患者来源的异种移植等模型成本高昂且劳动强度大。微流控技术可以提供小型化解决方案，以在实体瘤的三维复杂临床前模型中评估CAR-T疗法。在此，我们展示了一种新型微流控免疫测定法，用于评估CAR-T细胞对含有癌细胞和基质细胞的三维球体的细胞毒性和靶向特异性。通过监测CAR-T细胞与球体共培养物之间的相互作用，我们发现CAR-T细胞归巢至表达靶标的癌细胞并引发细胞毒性作用。在联合疗法中测试CAR-T细胞时，我们发现抗PD-L1疗法和卡铂化疗可增强CAR-T细胞的细胞毒性。我们提出这种概念验证微流控免疫测定法作为一种节省材料的临床前筛选工具，用于量化细胞疗法的疗效。
