Engineered immune cells, such as CAR-T cells, have transformed the treatment of certain blood cancers by enabling a patient's own immune system to recognize and destroy cancer cells. However, these therapies can also trigger dangerous inflammatory responses, known as cytokine release syndrome (CRS), which can be severe or even life-threatening. Current approaches to managing these side effects rely largely on medications that broadly suppress the immune response or completely shut down the therapeutic cells, potentially reducing treatment effectiveness.

We propose developing "smart" CAR-T cells that autonomously regulate their own activity through engineered feedback control circuits. By combining mathematical modeling with experimental validation, we will design cells that sense inflammatory signals and adjust their activity across multiple timescales—responding rapidly to prevent dangerous cytokine spikes while preserving their ability to eliminate cancer. Our interdisciplinary team brings together expertise in control engineering (Mayalu), synthetic biology and CAR-T engineering (Daniels), and clinical translation (Heitzeneder) to establish a model-guided framework for designing self-regulating cell therapies. This work aims to make CAR-T therapy safer, more effective, and more accessible by reducing toxic side effects and the need for intensive clinical monitoring, while establishing general design principles for engineering next-generation cell therapies.