title: Induction of leukemia-specific cytotoxic response by cross-presentation of late-apoptotic leukemic blasts by autologous dendritic cells of nonleukemic origin.
abstract: Acute myeloid leukemias (AMLs) are monoclonal proliferations of undifferentiated myeloid progenitors in blood and bone marrow. Long-term remissions are achieved in <50% of patients. There is hope that activation of specific antileukemic immune responses could efficiently eliminate minimal residual disease at the end of chemotherapy and decrease the frequency of relapses. It was demonstrated that AML leukemic blasts can acquire the morphology and phenotype of dendritic cells (DCs), i.e., differentiate into leukemic DCs. However, this method has limitations as a potential immunotherapy. The alternative approach for the induction of leukemia-specific cytotoxicity we explored in this study consisted of using DCs of nonleukemic origin, pulsed with autologous apoptotic leukemic blasts. We show that mature pulsed nonleukemic DCs were successfully generated from remission samples of all tested patients with minimal interindividual differences. Mature pulsed DCs were used as antigen-presenting cells for leukemia-specific CTL induction. Specific cytotoxic activity against autologous AML blasts was demonstrated. Tumor lysis was autologous blast specific, with no killing activity against allogeneic leukemic cells or autologous mature unpulsed DCs and was MHC class I and class II restricted. In one patient, autologous CTLs stimulated by leukemic DCs or pulsed nonleukemic DCs showed similar significant cytotoxic activity against autologous AML cells. These findings demonstrate the induction of leukemia-specific cytotoxic response by nonleukemic mature DCs cross-presenting apoptotic leukemic blasts and offer a complementary approach to the use of leukemic DCs. We believe that this strategy permits the generation of DC vaccines for the majority of patients with hematological malignancies.
authors.affiliation: INSERM U419, Institut de Biologie, 9 Quai Moncousu, 44093 Nantes Cedex 01, France.
authors.forename: Radek
authors.initials: R
authors.lastname: Spisek
authors.forename: Patrice
authors.initials: P
authors.lastname: Chevallier
authors.forename: Nadine
authors.initials: N
authors.lastname: Morineau
authors.forename: Noël
authors.initials: N
authors.lastname: Milpied
authors.forename: Herve
authors.initials: H
authors.lastname: Avet-Loiseau
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Harousseau
authors.forename: Khaled
authors.initials: K
authors.lastname: Meflah
authors.forename: Marc
authors.initials: M
authors.lastname: Gregoire
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D017951:Antigen Presentation / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007951:Leukemia, Myeloid / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*