MHC-independent leukemia antigens

MHC-independent leukemia antigens are a broad class of cell-surface molecules expressed on leukemic cells that can be recognized by therapeutic agents without the requirement for processing and presentation by the Major Histocompatibility Complex (MHC) [Nature Reviews Cancer, 2016]. This category includes well-characterized proteins such as CD19, CD20, CD22, CD33, and BCMA, which are targeted by monoclonal antibodies, antibody-drug conjugates, and Chimeric Antigen Receptor (CAR) T-cells [PubMed: 30635916]. Unlike MHC-restricted targets, such as neoantigens or cancer-testis antigens presented as peptides on HLA molecules, these antigens are directly accessible on the cell membrane, making them ideal for therapies that bypass the common tumor evasion strategy of MHC downregulation [PubMed: 31511301]. The clinical utility of targeting these antigens has revolutionized the treatment of hematologic malignancies, particularly in relapsed or refractory B-cell acute lymphoblastic leukemia and multiple myeloma [NIH, 2023]. However, because many of these antigens are also expressed on healthy hematopoietic cells, treatment often results in predictable "on-target, off-tumor" toxicities, such as B-cell aplasia or prolonged cytopenias [JCO, 2019]. Additionally, the high potency of MHC-independent cellular therapies can trigger systemic inflammatory responses, most notably cytokine release syndrome (CRS) and neurotoxicity [StatPearls, 2023]. Ongoing research aims to identify more specific antigens to minimize off-tumor effects and improve the durability of responses in myeloid malignancies [Nature Reviews Clinical Oncology, 2021].

Other names

Surface leukemia antigensNon-HLA restricted leukemia antigensCAR-T cell targets in leukemiaLeukemia-associated surface antigens

Direct binding of monoclonal antibodies, bispecific T-cell engagers (BiTEs), or Chimeric Antigen Receptors (CARs) to surface epitopes, leading to immune-mediated cell lysis, apoptosis, or delivery of cytotoxic payloads without the requirement for MHC-mediated peptide presentation.