Minor histocompatibility antigen TCR-T

Minor histocompatibility antigens (MiHA) are polymorphic peptides presented by HLA molecules on recipient cells in allogeneic hematopoietic cell transplantation (allo-HCT) and are derived from proteins with genetic variants that differ between recipient and donor. Following allo-HCT, hematopoietic-restricted MiHA enable selective targeting of residual recipient-derived hematopoiesis, including malignant cells. Advances in engineering T cells with high-affinity MiHA-specific T-cell receptors (TCR; TCR-T) are enabling clinical translation of MiHA T cell immunotherapy. Early-phase trials of HA-1 and HA-2-specific TCR-T demonstrate safety, persistence, and durable anti-leukemic activity in high-risk or relapsed disease. To accelerate translation, the field should expand TCR-T development to additional MiHA targets to broaden HLA and population coverage, integrate MiHA genotyping into donor selection, and devise platform trials to include patients with various MiHA/HLA genotypes and to efficiently test combination therapies. MiHA-directed TCR-T represents a genetically precise, potentially routine HCT adjunct that promises to fortify graft-versus-leukemia effects and improve relapse-free survival.