Antigen Targets for the Development of Immunotherapies in Leukemia

Abstract

Immunotherapeutic approaches, including allogeneic stem cell transplantation and donor lymphocyte infusion, have significantly improved the prognosis of leukemia patients. Further efforts are now focusing on the development of immunotherapies that are able to target leukemic cells more specifically, comprising monoclonal antibodies, chimeric antigen receptor (CAR) T cells, and dendritic cell- or peptide-based vaccination strategies. One main prerequisite for such antigen-specific approaches is the selection of suitable target structures on leukemic cells. In general, the targets for anti-cancer immunotherapies can be divided into two groups: (1) T-cell epitopes relying on the presentation of peptides via human leukocyte antigen (HLA) molecules and (2) surface structures, which are HLA-independently expressed on cancer cells. This review discusses the most promising tumor antigens as well as the underlying discovery and selection strategies for the development of anti-leukemia immunotherapies.

Keywords: HLA; T cell; antigen; epitope; immunotherapy; leukemia; peptide; target; vaccination.

Figure 1

Schematic overview of human leukocyte antigen (HLA)-independent and HLA-dependent antigen-specific cancer immunotherapy approaches. The HLA-independent approach focusses on antibody-based technologies targeting surface structures via e.g., monoclonal antibodies (mABs), bispecific antibodies (bsABs), chimeric antigen receptor (CAR) T cells, or antibody-drug conjugates (ADCs). HLA-dependent immunotherapies induce peptide-specific immune responses mainly by peptide-, RNA/DNA-, or dendritic cell (DC)-based vaccines, and adoptive transfer of activated or T-cell receptor-transduced T cells.

Figure 2

Schematic overview of the immunopeptidome-centric approach and the gene expression-based reverse immunology approach for the identification of HLA-presented peptides as targets for anti-cancer immunotherapy. A simplified depiction of the cellular processes involved in HLA antigen processing is illustrated, including (1) DNA transcription, (2) protein biosynthesis, (3) proteasomal degradation, and (4) peptide loading on HLA molecules via the endoplasmic reticulum and the Golgi apparatus, resulting in (5) the cell surface presentation of the HLA-peptide complex. The direct identification of naturally presented HLA-restricted peptides is based on the isolation of HLA-peptide complexes, followed by peptide purification, and peptide sequence identification by liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS). In contrast, the reverse immunology approach is based on DNA and/or RNA isolation and sequencing, followed by in silico epitope prediction of mutation-derived or overexpressed proteins.