Developing a cell therapy control switch

Nutrient-based safety switches can be applied to CAR-T, stem cell and TCR therapies

November 25, 2020
Mel J. Yeates

LONDON—This summer, Auxolytic Ltd. reported the publication of foundational research on its approach to cell therapy control switches in Nature Biotechnology.

In a paper entitled “Metabolic engineering generates a transgene-free safety switch for cell therapy,” Auxolytic—in collaboration with researchers at Stanford University School of Medicine—demonstrated that it had developed a novel safety “off” switch for various types of cell therapies.

This control switch method could potentially enable a physician to mitigate serious side effects when they are observed.

The switch works by knocking out a specific gene in the cell, creating a dependency on a particular nutrient for survival. In practice, patients would take a specific nutrient concurrent with cell therapy. If serious side effects were observed, the nutrient would be discontinued, which would deplete the cell therapy in the body and reduce or stop side effects.

“Cell therapies have been a breakthrough for the treatment of many diseases, but each type of cell therapy is associated with potential for very serious adverse events, which limits the number of patients who can benefit, often only being used in very ill or heavily pretreated patient groups,” says Dr. James Patterson, founder of Auxolytic and an author of the paper. “It’s our hope that our approach can make these therapies safer and more controlled, thus opening them up to patients who perhaps previously were not able to access them.”

“Given these challenges, we believe our approach to developing control switches could represent a completely novel way to improve the safety of cell therapy, without sacrificing the integrity of the original cells. We look forward to working with companies advancing groundbreaking cell therapies to improve their products and expand the number of patients who can benefit from them,” he noted.

While researchers have created some safeguards for cell therapies, the currently available options rely on the introduction of transgenes into the cell. This limits their application. Existing safeguards also exacerbate the instability of the cells by introducing additional genetic material.

“We applied the principle of auxotrophy, which is the engineered inability of an organism to synthesize a compound required for its survival, and have been able to successfully create human cells that are dependent on an externally supplied nutrient for their survival,” explains Patterson. “We believe this approach could be successfully applied to broaden the utility of groundbreaking cell therapies by mitigating some of the risks.”

In the study, researchers used genome-editing methods in pluripotent cells and primary human T cells to disrupt uridine monophosphate synthase (UMPS), the gene that naturally synthesizes the nutrient uridine. The UMPS-edited cells are dependent on the administration of external uridine for their proliferation, which enables control of cell growth by modulating the uridine supply. This approach was studied both in vitro and in vivo after transplantation in xenograft models.

“This approach is applicable across cell therapies theoretically, and we have so far tested it in pluripotent stem cells, primary human T cells and in a few human tumor cell lines,” Patterson points out. “The UMPS pathway also has manufacturing benefits, which is what led us to focus on this currently.”

“The nature of the UMPS pathway is such that it enables a manufacturing process which yields a 100-percent consistent cellular product dependent on external uridine for survival. This means we are creating a product where 100 percent of the cells require uridine to survive,” he continues. “There will not be a portion of unedited cells circulating in the body that cannot be ‘shut off’ if an adverse event happens.”

In the xenograft models, researchers tested both a cell therapy and pluripotent stem cells that had been edited to require uridine. The data demonstrate that when uridine administration was halted, the cells were inactive and unable to proliferate within a week.

“We’ve seen that depletion occurs over the time scale of a few days,” adds Patterson. “This was in an experiment where we withdrew nutrient-containing food from a mouse harboring human T cells. We’re now doing experiments to understand how reversible the switch is. It would be quite exciting if a physician could control the growth of cells in a patient by changing their uridine dosage. Current safety switches are all-or-nothing approaches, so doctors don’t have the ability to control cell therapy growth in their patients.”

To test whether the UMPS disruption approach could avoid graft versus host disease (GvHD), the researchers tested mice treated with UMPS-edited T cells, both with the addition of uridine and without. In mice who did not receive uridine, the cells did not survive and showed no GvHD.

“We’re also doing some exciting additional work around using our technology to engineer edited cells, and to select for specific engineered cell populations,” Patterson concludes. “We hope to be able to share this data soon.”

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