PML-RARA-targeted DNA vaccine induces protective immunity in a mouse model of leukemia.
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.
Padua
Rose Ann
RA
LBCH INSERM E0-03, U462 & U396, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, AP-HP 75010, Paris, France. rose.padua@kcl.ac.uk
Larghero
Jerome
J
Robin
Marie
M
le Pogam
Carol
C
Schlageter
Marie-Helene
MH
Muszlak
Sacha
S
Fric
Jan
J
West
Robert
R
Rousselot
Philippe
P
Phan
Thi Hai
TH
Mudde
Liesbeth
L
Teisserenc
Helene
H
Carpentier
Antoine F
AF
Kogan
Scott
S
Degos
Laurent
L
Pla
Marika
M
Bishop
J Michael
JM
Stevenson
Freda
F
Charron
Dominique
D
Chomienne
Christine
C
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
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