Austin J. Barrett

There have been major advances in our understanding of the multiple interactions between malignant cells and the innate and adaptive immune system. While the attention of immunologists has hitherto focused on solid tumors, the specific immunobiology of acute leukemias is now becoming defined. These discoveries have pointed the way to immune interventions building on the established graft-versus-leukemia (GVL) effect from hematopoietic stem-cell transplant (HSCT) and extending immunotherapy beyond HSCT to individuals with acute leukemia with a diversity of immune manipulations early in the course of the leukemia. At present, clinical results are in their infancy. In the coming years larger studies will better define the place of immunotherapy in the management of acute leukemias and lead to treatment approaches that combine conventional chemotherapy, immunotherapy and HSCT to achieve durable cures.

Summary: While chemotherapy is successful at inducing remission of acute myeloid leukaemia (AML), the disease has a high probability of relapse. Strategies to prevent relapse involve consolidation chemotherapy, stem cell transplantation and immunotherapy. Evidence for immunosurveillance of AML and susceptibility of leukaemia cells to both T cell and natural killer (NK) cell attack and justifies the application of immune strategies to control residual AML persisting after remission induction. Immune therapy for AML includes allogeneic stem cell transplantation, adoptive transfer of allogeneic or autologous T cells or NK cells, vaccination with leukaemia cells, dendritic cells, cell lysates, peptides and DNA vaccines and treatment with cytokines, antibodies and immunomodulatory agents. Here we describe what is known about the immunological features of AML at presentation and in remission, the current status of immunotherapy and strategies combining treatment approaches with a view to achieving leukaemia cure.

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. 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. 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.