A prime-editing platform could allow clinicians to control therapeutic T cells using immunosuppressive drugs already employed in clinical practice, according to a preclinical study.
The researchers engineered T cells to resist tacrolimus while retaining sensitivity to cyclosporin. Tacrolimus could therefore be used to suppress unedited immune cells while allowing the therapeutic cells to persist or expand. Cyclosporin could provide an alternative means of suppressing the edited cells if necessary.
The approach is intended for patients who require continued immunosuppression, including organ or stem cell transplant recipients and people with immune disorders. In these settings, drugs needed to control disease or prevent transplant rejection may also suppress therapeutic T cells.
“We’ve used genetic engineering to rewire these cells so clinicians could use existing drugs, already sitting in the hospital pharmacy, as a control dial,” said co-senior author Miles Horton in a press release. “Our aim was to build a platform around clinical reality, using medicines that clinicians already know and use.”
The team initially evaluated the platform using T cells from three patients with subcutaneous panniculitis-like T cell lymphoma with hemophagocytic lymphohistiocytosis. The rare immune-related cancer is associated with mutations in HAVCR2, which encodes the immune receptor TIM-3.
Prime editing corrected the pathogenic HAVCR2 variant in between 18.7 and 35.8 percent of patient-derived T cells. TIM-3 surface expression was restored in up to 44.4 percent of cells.
The researchers then performed two edits: correcting HAVCR2 and altering FKBP1A, which encodes a protein required for tacrolimus activity. In a humanized mouse model, tacrolimus provided a selective advantage to the multiplex-edited cells. After eight weeks, corrected HAVCR2 sequences represented an average of 76.8 percent of reads in the spleen, compared with 9.3 percent without tacrolimus selection.
The edited cells remained sensitive to cyclosporin, which acts through a different pathway. This retained susceptibility could provide a way to suppress the therapeutic population without requiring an additional experimental drug.
The researchers also applied the strategy to CD19-directed CAR T cells and cytomegalovirus-specific T cells. Edited CAR T cells retained viability, proliferation, and tumor-killing activity during tacrolimus exposure. In mice bearing CD19-positive tumors, the edited CAR T cells maintained tumor control under immunosuppression, whereas unedited cells did not.
Additional edits targeting resistance to methotrexate and mycophenolate demonstrated the platform’s potential adaptability, although resistance varied according to the specific edit.
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