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Developing thermo-activatable genetic circuits for immunotherapy

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In recent years, CAR-T cell therapy has revolutionized cancer immunotherapy, but there are still major obstacles preventing its broader applications in treating solid tumors. Challenges including on-target off-tumor toxicities increased the risks associated with CAR-T cell therapy and currently proposed strategies still lacked precise spatiotemporal control for CAR-T cell activation. To address this issue, we identified a calcium ion channel TRPV1 that is activated by heat and integrated it into an AND-gate inducible genetic circuits in HEK293T cells, to convert the TRPV1 thermal-activation into transcriptional activities. We first demonstrated heat-inducible luciferase reporter gene expression in engineered HEK293T cell line. We further engineered HEK293T cells to present tumor specific antigen CD19 upon heat activation and study the killing by anti-CD19 CAR-T cells. We showed that engineered HEK293T cells presented CD19 upon thermal-activation and were recognized and attacked by anti-CD19 CAR-T cells, demonstrating the feasibility of the system in immunotherapy. In the future, with a well-established focused ultrasound system, we hope to induce temperature changes in the confined volume of tissue in vivo to address the on-target off-tumor toxicities associated with current CAR-T cell therapies.

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This item is under embargo until June 27, 2024.