Neutrophil granule proteins as targets of leukemia-specific immune responses.
OBJECTIVE
Recent progress in the identification of leukemia antigens has stimulated the development of vaccines to treat hematological malignancies. Here we review the identification and characterization of the myeloid leukemia-specific antigens proteinase 3 and neutrophil elastase found in the primary (azurophil) granule proteins of granulocytes and their precursors. A peptide 'PR1' derived from these proteins induces powerful HLA-A0201-restricted CD8 T-cell proliferation. PR1-specific T cells are cytotoxic to leukemia and myelodysplastic syndrome progenitors, and occur at low frequencies in normal individuals. Frequencies are higher in patients with myeloid leukemias, and highest in patients with chronic myeloid leukemia entering molecular remission after allogeneic stem cell transplantation.


RESULTS
These observations, together with the known association of autoimmunity to proteinase 3 and neutrophil elastase in Wegener's granulomatosis, support the concept that there is a natural immunity to primary granule proteins which can be boosted to enhance immunity to leukemia. Preliminary reports indicate that PR1 peptide vaccination induces significant increases in PR1-specific cytotoxic T cells with rapid and durable remissions in some patients with advanced myeloid leukemias.


CONCLUSIONS
These promising developments in antileukemia vaccines have stimulated research to optimize vaccine delivery and modify regulation of natural T-cell immunity to primary granule proteins to improve treatment of otherwise refractory myeloid leukemias and myelodysplastic syndrome.
Barrett
John
J
Hematology Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA. barrettjj@mail.nih.gov
Rezvani
Katayoun
K
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000627:therapeutic use; D014890:Granulomatosis with Polyangiitis / Q000276:immunology / Q000473:pathology; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology* / Q000628:therapy; D009190:Myelodysplastic Syndromes / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D023461:Myeloid Progenitor Cells / Q000276:immunology / Q000473:pathology; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D022142:Secretory Vesicles / Q000276:immunology* / Q000378:metabolism
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines