From Pan-T-Cell Depletion to Selective Graft Engineering: Progress, Limitations, and Open Questions
4 affiliations
- 1Therapeutic Apheresis Service, Cell, Apheresis and Gene Therapies, NHS Blood and Transplant, Oxford OX3 9BQ, UK
- 2Oxford University Hospitals Transplant Unit, Churchill Hospital, Oxford OX3 7LE, UK
- 3Cellular and Molecular Therapies, Cell, Apheresis and Gene Therapies, NHS Blood and Transplant, Oxford OX3 9BQ, UK
- 4Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK
Abstract
The success of allogeneic haematopoietic stem cell transplantation is limited by three linked problems: graft-versus-host disease (GVHD), relapse, and infection. Pan-T-cell depletion, introduced in the 1980s, controlled GVHD but at the cost of relapse and impaired immune reconstitution. This trade-off has driven the field toward selective graft engineering, manipulating the donor graft’s cellular composition to separate GVHD-causing cells from those responsible for graft-versus-leukaemia (GVL) activity and infection control. This review traces that evolution, from CD34+ selection through αβ/CD19 depletion, naïve (CD45RA+) T-cell depletion, adoptive add-back, and gene-edited donor grafts, evaluated against current in vivo prophylaxis, principally post-transplant cyclophosphamide (PTCy). Selective graft-engineering platforms have achieved low rates of chronic GVHD and non-relapse mortality in defined settings. More recently, TREGZI (developed as Orca-T) received U.S. Food and Drug Administration (FDA) approval in June 2026 for adults with haematological malignancies undergoing matched-donor myeloablative allo-HSCT, following a randomised phase III trial against tacrolimus/methotrexate rather than PTCy. However, evidence for most other platforms remains dominated by single-arm, paediatric, or single-centre series; adult data are sparse, and no randomised trial has directly compared ex vivo graft engineering with optimised PTCy-based prophylaxis. Manufacturing infrastructure, cost, and access further limit adoption relative to established prophylaxis. Randomised trials are needed to determine whether, and for which patients, selective graft engineering offers a survival advantage.
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BibTeX
@article{sharplin2026from,
title = {{From Pan-T-Cell Depletion to Selective Graft Engineering: Progress, Limitations, and Open Questions}},
author = {Kirsty Sharplin and Sorur Moshgelgosha and Gurman Kaur},
journal = {Journal of Clinical Medicine},
year = {2026},
month = oct,
doi = {10.3390/jcm15218407},
url = {https://www.mdpi.com/2077-0383/15/21/8407},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - From Pan-T-Cell Depletion to Selective Graft Engineering: Progress, Limitations, and Open Questions
AU - Kirsty Sharplin
AU - Sorur Moshgelgosha
AU - Gurman Kaur
PY - 2026
DA - 2026/10/28
JO - Journal of Clinical Medicine
DO - 10.3390/jcm15218407
UR - https://www.mdpi.com/2077-0383/15/21/8407
AB - The success of allogeneic haematopoietic stem cell transplantation is limited by three linked problems: graft-versus-host disease (GVHD), relapse, and infection. Pan-T-cell depletion, introduced in the 1980s, controlled GVHD but at the cost of relapse and impaired immune reconstitution. This trade-off has driven the field toward selective graft engineering, manipulating the donor graft’s cellular composition to separate GVHD-causing cells from those responsible for graft-versus-leukaemia (GVL) activity and infection control. This review traces that evolution, from CD34+ selection through αβ/CD19 depletion, naïve (CD45RA+) T-cell depletion, adoptive add-back, and gene-edited donor grafts, evaluated against current in vivo prophylaxis, principally post-transplant cyclophosphamide (PTCy). Selective graft-engineering platforms have achieved low rates of chronic GVHD and non-relapse mortality in defined settings. More recently, TREGZI (developed as Orca-T) received U.S. Food and Drug Administration (FDA) approval in June 2026 for adults with haematological malignancies undergoing matched-donor myeloablative allo-HSCT, following a randomised phase III trial against tacrolimus/methotrexate rather than PTCy. However, evidence for most other platforms remains dominated by single-arm, paediatric, or single-centre series; adult data are sparse, and no randomised trial has directly compared ex vivo graft engineering with optimised PTCy-based prophylaxis. Manufacturing infrastructure, cost, and access further limit adoption relative to established prophylaxis. Randomised trials are needed to determine whether, and for which patients, selective graft engineering offers a survival advantage.
SN - 2077-0383
ER -