Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, 90089, USA.
Department of Immunology and Pathogenesis, College of Letters and Science, University of California, Berkeley, CA, 94720, USA.
Adv Healthc Mater. 2019 Mar;8(5):e1900001. doi: 10.1002/adhm.201900001. Epub 2019 Feb 8.
Despite its revolutionary success in hematological malignancies, chimeric antigen receptor T (CAR-T) cell therapy faces disappointing clinical results in solid tumors. The poor efficacy has been partially attributed to the lack of understanding in how CAR-T cells function in a solid tumor microenvironment. Hypoxia plays a critical role in cancer progression and immune editing, which potentially results in solid tumors escaping immunosurveillance and CAR-T cell-mediated cytotoxicity. Mechanistic studies of CAR-T cell biology in a physiological environment has been limited by the complexity of tumor-immune interactions in clinical and animal models, as well as by a lack of reliable in vitro models. A microdevice platform that recapitulates a 3D tumor section with a gradient of oxygen and integrates fluidic channels surrounding the tumor for CAR-T cell delivery is engineered. The design allows for the evaluation of CAR-T cell cytotoxicity and infiltration in the heterogeneous oxygen landscape of in vivo solid tumors at a previously unachievable scale in vitro.
尽管嵌合抗原受体 T (CAR-T) 细胞疗法在血液恶性肿瘤方面取得了革命性的成功，但在实体肿瘤中的临床效果却令人失望。疗效不佳的部分原因是人们对 CAR-T 细胞在实体瘤微环境中的作用机制了解不足。缺氧在癌症进展和免疫编辑中起着关键作用，这可能导致实体肿瘤逃避免疫监视和 CAR-T 细胞介导的细胞毒性。由于临床和动物模型中肿瘤-免疫相互作用的复杂性，以及缺乏可靠的体外模型，对 CAR-T 细胞生物学在生理环境中的机制研究受到了限制。设计了一种微器件平台，该平台可再现具有氧梯度的 3D 肿瘤切片，并整合围绕肿瘤的流体通道，用于 CAR-T 细胞递送。该设计允许以前所未有的体外规模评估 CAR-T 细胞在体内实体肿瘤异质氧环境中的细胞毒性和浸润。
