Evaluating CAR‐T Cell Therapy in a Hypoxic 3D Tumor Model

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. Hypoxia is a feature of most solid tumor microenvironments. Chimeric antigen receptor T (CAR‐T) cell therapy has not been successful in solid tumors, partially due to the tumor microenvironment. An in vitro hypoxic tumor model with an oxygen gradient is engineered, which allows for quantitative assessment of CAR‐T cell cytotoxicity and infiltration under the heterogeneous oxygen landscape in solid tumors.