Minor histocompatibility antigens and leukemia-associated antigens (mHag/LAA)

Minor histocompatibility antigens (mHags) and leukemia-associated antigens (LAAs) are peptides derived from intracellular proteins that are presented on the cell surface by Major Histocompatibility Complex (MHC) molecules. These peptide-MHC complexes serve as the primary targets for T-cell receptors (TCRs), allowing the immune system to distinguish between healthy and malignant or foreign cells (Bleakley & Riddell, 2011, Nature Reviews Cancer). In the treatment of hematologic malignancies, particularly following allogeneic stem cell transplantation, mHags and LAAs are exploited to induce a graft-versus-leukemia (GvL) effect (Griffioen et al., 2016, Frontiers in Immunology). mHags arise from genetic polymorphisms between donor and recipient, while LAAs are proteins like WT1 or PRAME that are overexpressed in leukemic blasts (Rezvani et al., 2008, Blood). Therapeutic interventions include the development of TCR-engineered T cells (TCR-T) and vaccines designed to enhance the T-cell response against these specific complexes. These therapies aim to provide a highly specific anti-tumor response with minimal damage to healthy tissues. However, the high degree of patient specificity and HLA restriction presents significant challenges for broad clinical application. Notable safety concerns include the risk of graft-versus-host disease (GvHD) if the target antigen is expressed in non-malignant recipient tissues (Warren et al., 2017, Blood).

Other names

mHagsLAAsMinor histocompatibility antigensLeukemia-associated antigensTCR-peptide-MHC targetsTumor-associated antigens

TCR-engineered T cells or endogenous T cells recognize specific peptide-MHC complexes on the surface of leukemia cells, leading to the formation of an immunological synapse, release of perforin and granzymes, and subsequent apoptosis of the target cell.