Neoantigens in Hematologic Malignancies

Abstract

T cell cancer neoantigens are created from peptides derived from cancer-specific aberrant proteins, such as mutated and fusion proteins, presented in complex with human leukocyte antigens on the cancer cell surface. Because expression of the aberrant target protein is exclusive to malignant cells, immunotherapy directed against neoantigens should avoid "on-target, off-tumor" toxicity. The efficacy of neoantigen vaccines in melanoma and glioblastoma and of adoptive transfer of neoantigen-specific T cells in epithelial tumors indicates that neoantigens are valid therapeutic targets. Improvements in sequencing technology and innovations in antigen discovery approaches have facilitated the identification of neoantigens. In comparison to many solid tumors, hematologic malignancies have few mutations and thus fewer potential neoantigens. Despite this, neoantigens have been identified in a wide variety of hematologic malignancies. These include mutated nucleophosmin1 and PML-RARA in acute myeloid leukemia, ETV6-RUNX1 fusions and other mutated proteins in acute lymphoblastic leukemia, BCR-ABL1 fusions in chronic myeloid leukemia, driver mutations in myeloproliferative neoplasms, immunoglobulins in lymphomas, and proteins derived from patient-specific mutations in chronic lymphoid leukemias. We will review advances in the field of neoantigen discovery, describe the spectrum of identified neoantigens in hematologic malignancies, and discuss the potential of these neoantigens for clinical translation.

Keywords: T cell receptor; fusion proteins; hematologic malignancies; human leukocyte antigen; immunotherapy; mutations; neoantigen.