Patient-specific leukemia-associated antigen peptide-MHC complex (pMHC-LAA)

Patient-specific leukemia-associated antigens (LAAs) presented on peptide-MHC (pMHC) complexes are a specialized class of immunotherapy targets that allow the immune system to recognize intracellular proteins within leukemia blasts [1]. These targets are formed when proteins such as Wilms Tumor 1 (WT1) or PRAME are processed into short peptides and displayed on the cell surface by Human Leukocyte Antigen (HLA) molecules [2]. Because these peptides are often derived from proteins that are overexpressed or mutated specifically in malignant cells, they provide a high degree of selectivity for therapeutic intervention [3]. Current drug development focuses on T-cell receptor (TCR)-engineered T cells and TCR-like antibodies that can bind these complexes with high affinity, triggering a potent cytotoxic immune response against the leukemia [4]. However, the effectiveness of these therapies is highly dependent on the patient's specific HLA genotype and the stability of antigen presentation, which can be compromised by tumor escape mechanisms such as HLA downregulation [5]. [1] Schuster, H., et al. (2017). "The immunopeptidomic landscape of myeloid leukemias." Nature Communications. [2] Anguille, S., et al. (2012). "Leukemia-associated antigens as targets for active tumor immunotherapy." Leukemia. [3] Dao, T., et al. (2013). "Targeting the intracellular WT1 oncogene product with a therapeutic human antibody." Science Translational Medicine. [4] Hofmann, S., et al. (2019). "TCR-like antibodies for cancer therapy." Frontiers in Oncology. [5] Dhatchinamoorthy, K., et al. (2021). "Mechanisms of MHC I downregulation in cancer." Frontiers in Immunology.

Other names

Leukemia-associated antigen (LAA)pHLA complexpMHC complexTumor-specific antigen (TSA)Minor histocompatibility antigen (mHag)Neoantigen-MHC complex

T-cell receptor (TCR) mediated recognition of peptide-MHC complexes leading to MHC-restricted T-cell activation and direct tumor cell lysis.