A 'safety switch' for cell therapy based on nutrient deprivation

The early success of CAR-T cell therapies in treating some forms of blood cancer has sent oncology researchers on a quest to develop the technology to address a range of tumor types. But the risk that the modified immune cells could cause the potentially deadly side effect known as cytokine release syndrome has prompted an equally enthusiastic effort in the research community to find innovative ways to combat that problem.

London-based startup Auxolytic is developing “safety switches” for cell therapy that hinge on depriving them of nutrients they need to survive. The company was founded by University of Cambridge biochemist James Patterson, Ph.D., who is working with researchers at Stanford University to develop the switch.

In a new study, the researchers demonstrated their technique with a gene called UMPS that normally makes the nutrient uridine, which T cells need to grow and proliferate. When they knocked out the gene in human T cells and pluripotent stem cells, the cells became inactive within a week, they reported in the journal Nature Biotechnology.

How would this work in people? The UMPS gene would be knocked out in the cell therapy during the engineering process, and then the patient receiving the treatment would take uridine supplements to replace the missing nutrient. If signs of side effects to the cell therapy emerge, the patient would stop taking the supplement.

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Auxolytic tested its technology in mice by treating them with UMPS-edited T cells and then monitoring them for the rejection response graft versus host disease (GvHD). The cells became inactive in the mice that were not fed uridine supplements.

It’s the latest idea to emerge for improving the safety of cell therapies. Earlier this year, a team at the University of North Carolina at Chapel Hill published a study showing they could dampen cytokine release syndrome by modulating levels of an enzyme called SHP1. Last year, German scientists showed that Bristol Myers Squibb’s leukemia drug Sprycel could temporarily pause the activity of CAR-T cells in mice, preventing cytokine release.

Auxolytic gets its name from a scientific principle called “auxotrophy,” which refers to the ability of cells to synthesize nutrients and other compounds they need to survive, Patterson explained in a statement. Patterson’s goal is to work with CAR-T developers to incorporate the technology into their products, he said.