-Safety switches can be applied to CAR T, stem cell and TCR Therapies -
-Cells are created using a gene knockout, maintaining stability of the cells, avoiding additional genetic material and immunogenicity -
-Manufacturing process enables 100% population of cells with a safety switch -
Cambridge, Mass. – Auxolytic, a company developing novel nutrient-based control switches to address safety issues associated with cellular therapies, today announced the publication of foundational research on its approach in Nature Biotechnology. In the paper, entitled "Metabolic engineering generates a transgene-free safety switch for cell therapy,” Auxolytic, in collaboration with researchers at Stanford University School of Medicine, demonstrates that it has developed a novel safety “off” switch for various types of cell therapies, potentially enabling 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 its survival. In practice, patients would take a specific nutrient concurrent with the cell therapy. If serious side effects were observed, the nutrient would be discontinued, thus depleting the cell therapy in the body and reducing or stopping the 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,” said James Patterson, MB, Ph.D. and Founder of Auxolytic and author on the paper. “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.”
Summary of the Paper:
While researchers have come up with some safeguards for cell therapies, all currently available options rely on the introduction of transgenes into the cell. This limits their application owing to immunogenicity or transgene silencing. Existing safeguards also exacerbate the instability of the cells by introducing additional genetic material. In the paper, researchers describe their work using genome editing methods in both pluripotent cells and primary human T cells, to disrupt uridine monophosphate synthase (UMPS), which is the gene that naturally synthesizes the nutrient uridine. The UMPS-edited cells are dependent on the administration of external uridine for their proliferation, enabling the control of their growth by modulating uridine supply. This approach was studied both in vitro and in vivo after transplantation in xenograft models.
· In 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 one week.
· To test whether this approach could avoid graft versus host disease (GvHD), the team tested mice treated with UMPS-edited T cells, both with the addition of uridine and without and demonstrated that in mice who did not receive uridine, the cells did not survive, and showed no GvHD.
· The paper also outlines that nature of the UMPS pathway enables a manufacturing process which yields a 100% consistent cellular product dependent on external uridine for survival.
“There are several approaches to developing synthetic control switches for cell therapies, and some have enabled the control of severe side effects. However, all of these approaches require new genetic material be introduced in the cell, which is associated with the potential for immunogenicity, cells escaping the switch and remaining active due to genetic instability, and manufacturing issues,” continued Dr. Patterson. “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. We believe this approach could be successfully applied to broaden the utility of groundbreaking cell therapies by mitigating some of the risks.”
The lead author of the paper is Volker Wiebking, Dr. med., postdoctoral research fellow in the pediatrics department, and senior author is Matthew Porteus, MD, Ph.D., professor of pediatrics, both of the Stanford University School of Medicine.