Walter and Eliza Hall Institute researchers engineer T-cell platform
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 Dr. Miles Horton.
Australian researchers have engineered a gene-editing platform utilizing prime editing that allows clinicians to control therapeutic T cells using existing immunosuppressive drugs as a regulatory dial, according to a study published in Blood.
Cell and gene therapies traditionally involve extracting a patient’s immune cells, modifying them in a laboratory setting, and reintroducing them into the body. Once inside the patient, however, clinicians face significant limitations in selectively boosting or suppressing those engineered cells. This hurdle affects individuals requiring ongoing immunosuppression, including organ or stem cell transplant recipients, patients battling severe infections, and those receiving cell therapies for cancer. The immunosuppressive drugs necessary to protect a transplanted organ or control underlying disease frequently suppress the therapeutic cells patients require to survive.
Rewiring T Cells for Dual-Drug Control
Researchers at the Walter and Eliza Hall Institute developed a prime-editing platform to make therapeutic T cells resistant to the immunosuppressive drug tacrolimus while remaining sensitive to cyclosporin.
The precise drug-control mechanism allows clinicians to administer one medication to protect corrected cells while suppressing other immune elements, keeping a secondary drug available to wind back the edited cells if necessary. Published in the journal Blood, the study successfully demonstrated the platform across subcutaneous panniculitis-like T-cell lymphoma with HLH, virus-specific T cells, and CAR T-cell therapies.
Dr. Horton, a researcher at the Walter and Eliza Hall Institute and pediatrics resident at the Royal Children’s Hospital, stated that the team addressed a practical clinical dilemma. He noted that other experimental approaches require adopting both a novel cell therapy and an unfamiliar drug simultaneously, whereas this platform builds around existing hospital inventories.
Preclinical Tests Target Rare Blood Cancers and Infections
During preclinical tests, the team programmed T cells to resist tacrolimus while preserving sensitivity to cyclosporin. This distinction grants clinicians a functional dual-drug strategy. One drug supports the survival of the engineered cells while suppressing unwanted immune activity, and the alternative drug remains available to eliminate or reduce the modified cells if they behave unexpectedly.
The study specifically examined subcutaneous panniculitis-like T-cell lymphoma with HLH (SPTCL-HLH), a rare and serious immune-related blood cancer affecting children and young adults. Researchers utilized cells from patients with the condition, applying prime editing to correct the disease-causing mutation and insert a second edit conferring resistance to tacrolimus. The platform subsequently underwent testing in virus-specific T cells designed to assist transplant recipients in fighting infections without interrupting anti-rejection regimens, alongside CAR T-cell therapies utilized in oncology.
Translating Lab Innovation Into Routine Care
Dr. Tom Lew, a co-senior author, researcher at the Walter and Eliza Hall Institute, and clinical hematologist at the Peter MacCallum Cancer Centre and the Royal Melbourne Hospital, emphasized the clinical rationale behind the design.
As clinicians, we are always thinking about whether a promising technology could realistically fit into patient care,
Dr. Lew said. Our approach is built around medicines that are already part of routine clinical practice, which could make translation more practical.
Next Steps Toward First-in-Human Trials
Dr. Esther Bandala-Sanchez, first author of the study, noted the platform could be adapted for multiple types of treatment.
We showed this strategy could be applied across different types of therapeutic T cells, not just one disease setting,
Dr. Bandala-Sanchez said. The edited cells stayed functional under immunosuppression, and importantly, remained sensitive to other drugs. That precision is what makes the platform so promising as a foundation for future cell therapies.
The research team is advancing toward a first-in-human clinical trial. The study was conducted with collaborators from the Walter and Eliza Hall Institute, Peter MacCallum Cancer Centre, Royal Melbourne Hospital, Westmead Hospital, the University of Sydney, and Austin Health, with financial backing from the National Health and Medical Research Council, the Victorian State Government, the Jack Brockhoff Foundation, the Ramaciotti Foundation, and the Watt Mirisklavos Foundation.
Disclaimer: The information provided in this article is for educational and scientific communication purposes only and does not constitute medical advice. Always consult with a qualified healthcare provider regarding any medical condition, diagnosis, or treatment plan.