Nature Medicine
9, 1413 - 1417 (2003)
Published online: 19 October 2003; | doi:10.1038/nm949
PML-RARA−targeted DNA vaccine induces protective immunity in a mouse model of leukemiaRose Ann Padua1, 2, Jerome Larghero1, Marie Robin1, Carol le Pogam1, Marie-Helene Schlageter1, Sacha Muszlak2, Jan Fric1, Robert West3, Philippe Rousselot1, Thi Hai Phan1, Liesbeth Mudde1, Helene Teisserenc1, Antoine F Carpentier1, Scott Kogan4, Laurent Degos1, Marika Pla1, J Michael Bishop5, Freda Stevenson6, Dominique Charron1
& Christine Chomienne11
LBCH INSERM E0-03, U462 & U396, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, AP-HP 75010, Paris, France. 2
Department of Hematological Medicine, King's College London, London SE5 9NU, UK. 3
Wales Heart Research Institute, University of Wales College of Medicine, Cardiff CF14 4XN, UK. 4
Cancer Center, University of California, San Francisco, California 94143, USA. 5
G.W. Hooper Foundation, University of California, San Francisco, California 94143, USA. 6
Tenovus, Southampton University, Southampton, S016 6YD, UK.
Correspondence should be addressed to Rose Ann Padua rose.padua@kcl.ac.ukDespite 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- (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- (IFN-). 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.
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