Yan Leyfman, Medical Correspondent at OncLive, Freelance, Co-Founder and Executive Director of MedNews Week, shared on X:
“What if immunosuppressive drugs could become tools to control therapeutic T cells rather than simply suppress them?
A major challenge in cell and gene therapy is the lack of clinically practical ways to selectively expand or eliminate engineered cells inside the body.
This becomes particularly important when patients cannot discontinue immunosuppression, such as transplant recipients or individuals with immune dysregulation.
A new study introduces a multiplex prime-editing platform that turns commonly used immunosuppressive drugs into pathway-specific switches for controlling therapeutic T cells in vivo.
The investigators demonstrated several important applications:
- Correcting pathogenic mutations: Prime editing corrected multiple immune dysregulation-associated variants in primary human T cells, including the HAVCR2 driver mutation in cells from patients with subcutaneous panniculitis-like T-cell lymphoma (SPTCL).
- Selective expansion: Combining gene correction with drug-resistance editing enabled corrected SPTCL T cells to expand selectively under immunosuppressive pressure in humanized mouse models.
- Reversible control: These engineered cells retained sensitivity to alternative agents, providing a potential mechanism for rapid in vivo suppression.
- Broader applicability: Drug-resistant antigen-specific and CAR T cells maintained effector function despite pharmacologic immunosuppression. Importantly, genomic, transcriptional, immunophenotypic, and clonal analyses demonstrated minimal off-target perturbation in the studied systems.
The implications extend beyond correcting inherited or acquired immune dysfunction. This strategy could help make CAR-T and other cellular therapies compatible with clinical settings in which immunosuppression is unavoidable.
The conceptual shift is significant:
Instead of asking patients to stop immunosuppression to protect therapeutic cells, we may be able to engineer therapeutic cells to function within – and be selectively controlled by – that immunosuppressive environment.
These remain preclinical findings, but they introduce a compelling framework for more controllable, adaptable cell therapies.”
Title: Prime editing enables drug-controllable T-cell therapies with clinical immunosuppression
Authors: Esther Bandala-Sanchez, Emma V. Petley, Kerry Ramsay, Adrienne Hilton, Christine White, Naiara G. Bediaga, Connie S. Li Wai Suen, Shalin H. Naik, Ashleigh S. Davey, Matthew E. Call, Melissa J. Call, Carrie van der Weyden, Lucy C. Fox, David Ritchie, Gaurav Sutrave, Kenneth Micklethwaite, David Gottlieb, Samantha Chan, Andrew W. Roberts, Charlotte Slade, Thomas E. Lew, Miles B. Horton
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