Neoantigens in Hematological Malignancies-Ultimate Targets for Immunotherapy?

Abstract

Neoantigens derive from non-synonymous somatic mutations in malignant cells. Recognition of neoantigens presented via human leukocyte antigen (HLA) molecules on the tumor cell surface by T cells holds promise to enable highly specific and effective anti-cancer immune responses and thus neoantigens provide an exceptionally attractive target for immunotherapy. While genome sequencing approaches already enable the reliable identification of somatic mutations in tumor samples, the identification of mutation-derived, naturally HLA-presented neoepitopes as targets for immunotherapy remains challenging, particularly in low mutational burden cancer entities, including hematological malignancies. Several approaches have been utilized to identify neoepitopes from primary tumor samples. Besides whole genome sequencing with subsequent in silico prediction of potential mutation-derived HLA ligands, mass spectrometry (MS) allows for the only unbiased identification of naturally presented mutation-derived HLA ligands. The feasibility of characterizing and targeting these novel antigens has recently been demonstrated in acute myeloid leukemia (AML). Several immunogenic, HLA-presented peptides derived from mutated Nucleophosmin 1 (NPM1) were identified, allowing for the generation of T-cell receptor-transduced NPM1^mut-specific T cells with anti-leukemic activity in a xenograft mouse model. Neoantigen-specific T-cell responses have also been identified for peptides derived from mutated isocitrate dehydrogenase (IDH^mut), and specific T-cell responses could be induced by IDH^mut peptide vaccination. In this review, we give a comprehensive overview on known neoantigens in hematological malignancies, present possible prediction and discovery tools and discuss their role as targets for immunotherapy approaches.

Keywords: HLA antigens; NPM1 mutations; hematological malignancies; immunopeptidomics; mass spectrometry; neoantigens.

Figure 1

Origins of neoantigens. Schematic overview showing different origins of neoantigens with prominent examples in hematological malignancies. AML, acute myeloid leukemia; FLT3, FMS like tyrosine kinase 3; HLA, human leukocyte antigen; NPM1, nucleophosmin 1; IDH, isocitrate dehydrogenase; MPN, myeloproliferative neoplasia; CALR, calreticulin; JAK2 janus like kinase 2; CML, chronic myeloid leukemia; CLL, chronic lymphocytic leukemia; MCL, mantle cell lymphoma; Ig, immunoglobulin.