Chimeric antigen receptor-T cell efficacy can be evaluated on an Organ-Chip model system

Abstract Objective: The need for human-centric model systems that can test the efficacy of chimeric antigen receptor (CAR) therapies is expanding rapidly, as these hold great promise for cancer treatment. We recently developed a system for inflammatory immune cell recruitment on the human Colon Intestine-Chip as a model for inflammatory bowel disease (IBD). The goal of the current study was to develop a novel system for measuring the recruitment and killing capacity of CAR-T cells in an Organ-Chip system. Methods: We seeded a representative human HER2 +non-small cell lung carcinoma cell line (A549) into the top channel and human lung microvascular endothelial cells into the vascular (bottom) channel of Emulate’s S1 Organ-Chips. HER2-specific or CD19-specific (negative control) CAR-T cells were perfused through the vascular channel. Total CAR-T cell recruitment from the vasculature channel to the carcinoma-containing (top) channel and CAR-T-mediated killing (caspase activity, and IFN-g production) were measured over 72 hours. This system is further being used to monitor CAR-T cell exhaustion and efficacy of co-therapies (e.g., that might support CAR-T recruitment and killing efficacy). Results: HER2 CAR-T cells were recruited to the top channel, which was supported by the addition of known cancer chemokines (e.g. CXCL10), and induced significant killing and response to co-therapies as measured by caspase activity compared to controls. Conclusion: These early findings suggest that the human-centric Organ-Chip model can evaluate the efficacy of CAR-T cell therapies, and in particular, provide a system that integrates both the recruitment and killing aspects of CAR-T function.