Graft-versus-leukaemia antigen discovery utilising the bone marrow T cell repertoire in patients with acute myeloid leukaemia

Thesis

Acute myeloid leukaemia (AML) is a highly aggressive haematological malignancy for which allogeneic stem cell transplantation (alloSCT) remains the most effective curative therapy. Durable disease control relies on the graft-versus-leukaemia (GvL) effect, where donor-derived T cells eradicate residual leukaemia. Despite over 60 years of clinical use, the identity and dynamics of GvL-specific T cells remain poorly defined, with limited investigation into the early post-alloSCT bone marrow, at a time when relapse risk is greatest.

Using a high-risk, GvL-enriched patient cohort, novel methodological platforms were developed to overcome the limited viability and proliferative capacity of early post-alloSCT bone marrow, enabling the detection and characterisation of rare antigen-specific T cells. Across complementary approaches, multiple GvL clonotypes recognising minor histocompatibility antigens were detected at frequencies as low as 0.01% and shown to persist for years across marrow and blood compartments. Importantly, four clonotypes were identified directly ex vivo, providing unambiguous evidence for their in vivo presence. Phenotypic profiling showed that GSTZ1-specific T cells adopted a Th1-polarised central memory state consistent with long-term surveillance, while functional testing validated a METTL22-specific CD4+ clonotype as an HLA-DR-restricted response that was selective for a patient-derived variant.

These findings establish that GvL immunity can be detected in the marrow within the first post-alloSCT year, persists long-term despite extreme rarity and includes CD4⁺ T cell subsets with durable effector potential. By expanding the catalogue of validated GvL responses and providing a framework for their detection in the bone marrow, this work advances the understanding of the cellular basis of GvL to inform future developments within the field of transplant immunology.

Authors: Tseu, BS

• DOI: 10.5287/ora-n1j6bqkrp
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: acute myeloid leukaemia; graft-vs-leukaemia
• Subjects: Acute myeloid leukemia; Clinical immunology; Transplantation of organs, tissues, etc.; Haematology