title: PML-RARA-targeted DNA vaccine induces protective immunity in a mouse model of leukemia.
abstract: Despite improved molecular characterization of malignancies and development of targeted therapies, acute leukemia is not curable and few patients survive more than 10 years after diagnosis. Recently, combinations of different therapeutic strategies (based on mechanisms of apoptosis, differentiation and cytotoxicity) have significantly increased survival. To further improve outcome, we studied the potential efficacy of boosting the patient's immune response using specific immunotherapy. In an animal model of acute promyelocytic leukemia, we developed a DNA-based vaccine by fusing the human promyelocytic leukemia-retinoic acid receptor-alpha (PML-RARA) oncogene to tetanus fragment C (FrC) sequences. We show for the first time that a DNA vaccine specifically targeted to an oncoprotein can have a pronounced effect on survival, both alone and when combined with all-trans retinoic acid (ATRA). The survival advantage is concomitant with time-dependent antibody production and an increase in interferon-gamma (IFN-gamma). We also show that ATRA therapy on its own triggers an immune response in this model. When DNA vaccination and conventional ATRA therapy are combined, they induce protective immune responses against leukemia progression in mice and may provide a new approach to improve clinical outcome in human leukemia.
authors.affiliation: LBCH INSERM E0-03, U462 & U396, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, AP-HP 75010, Paris, France. rose.padua@kcl.ac.uk
authors.forename: Rose Ann
authors.initials: RA
authors.lastname: Padua
authors.forename: Jerome
authors.initials: J
authors.lastname: Larghero
authors.forename: Marie
authors.initials: M
authors.lastname: Robin
authors.forename: Carol
authors.initials: C
authors.lastname: le Pogam
authors.forename: Marie-Helene
authors.initials: MH
authors.lastname: Schlageter
authors.forename: Sacha
authors.initials: S
authors.lastname: Muszlak
authors.forename: Jan
authors.initials: J
authors.lastname: Fric
authors.forename: Robert
authors.initials: R
authors.lastname: West
authors.forename: Philippe
authors.initials: P
authors.lastname: Rousselot
authors.forename: Thi Hai
authors.initials: TH
authors.lastname: Phan
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Mudde
authors.forename: Helene
authors.initials: H
authors.lastname: Teisserenc
authors.forename: Antoine F
authors.initials: AF
authors.lastname: Carpentier
authors.forename: Scott
authors.initials: S
authors.lastname: Kogan
authors.forename: Laurent
authors.initials: L
authors.lastname: Degos
authors.forename: Marika
authors.initials: M
authors.lastname: Pla
authors.forename: J Michael
authors.initials: JM
authors.lastname: Bishop
authors.forename: Freda
authors.initials: F
authors.lastname: Stevenson
authors.forename: Dominique
authors.initials: D
authors.lastname: Charron
authors.forename: Christine
authors.initials: C
authors.lastname: Chomienne
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D015514:Oncogene Proteins, Fusion / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D014212:Tretinoin / Q000494:pharmacology; D019444:Vaccines, DNA / Q000276:immunology* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D019444:Vaccines, DNA; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin