Development in Synthetic Biology for Safe and Controlled CAR-T Cell Therapy

There are promising results of adoptive T cell therapy, particularly chimeric antigen receptor T (CAR-T) cell therapy, in treating various malignancies; however, safety concerns such as cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS), and on-target off-tumor (OTOT) toxicity have emerged, prompting the application of synthetic biology to address these challenges. A recent review published by Science takes a step back and assess the current state of the field.

The activation intensity of CAR-T cells is pivotal for effectiveness, leading to modifications incorporating costimulatory molecules. Yet, these changes often yield pronounced adverse effects. Current clinical approaches using interleukin-6 (IL-6) and IL-1 receptor antagonists may impact normal immune function.

Synthetic biology, characterized by its systematic, modular, and standardised engineering, becomes a solution: by manipulating molecular components, it enables modular control of CAR-T cell behaviour, ensuring safety across temporal and spatial dimensions.

Looking to the future, the rapid advancement of synthetic biology has produced sensors and gene circuits, showcasing promising outcomes in clinical trials for CAR-T cells. However, challenges like immunogenicity, expression leakage, and technical limitations persist. Future efforts must concentrate on minimizing immunogenicity, addressing gene circuit leakage, and enhancing gene delivery efficiency.

Anticipate a future where CAR-T cells undergo sophisticated engineering, with synthetic biology providing diverse components, logic gates, and genetic circuits. The focus on universal CAR-T cells necessitates modifications to enhance safety. Thorough investigations into adverse effects are crucial for the development of safer, controllable, intelligent, and universal CAR-T cell therapies in future clinical treatments.