Research Papers: Immunology:
DNA-mediated adjuvant immunotherapy extends survival in two different mouse models of myeloid malignancies
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Carole Le Pogam1,2, Satyananda Patel1,2, Petra Gorombei1,2, Laura Guerenne1,2, Patricia Krief1,2, Nader Omidvar4, Nilgun Tekin5, Elena Bernasconi1,2, Flore Sicre1,2,3, Marie-Helene Schlageter1,2,3, Martine Chopin6, Maria-Elena Noguera3, Robert West7, Ansu Abu8, Vikram Mathews8, Marika Pla1,2, Pierre Fenaux1,2,3, Christine Chomienne1,2,3 and Rose Ann Padua1,2,3
1 Unité Mixte de la Recherche de Santé (UMR-S), Institut Universitaire d’Hématologie, Université Paris Diderot, Paris, France
2 Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U), Paris, France
3 Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
4 Haemotology Department, Cardiff University School of Medicine, Cardiff, UK
5 Biotechnology Institute, Ankara University, Ankara, Turkey
6 Département d’Expérimentation Animale, Institut Universitaire d’Hématologie, University Paris Diderot, Paris, France
7 Welsh Heart Research Institute, Cardiff University School of Medicine, Cardiff, UK
8 Department of Hematology, Christian Medical College and Hospital, Vellore, India
Rose Ann Padua, email:
Keywords: plasmid DNA based immunotherapy, MDS, APL, memory T-cells, Immunology and Microbiology Section, Immune response, Immunity
Received: July 12, 2015 Accepted: August 14, 2015 Published: September 10, 2015
We have previously shown that a specific promyelocytic leukemia-retinoic acid receptor alpha (PML-RARA) DNA vaccine combined with all-trans retinoic acid (ATRA) increases the number of long term survivors with enhanced immune responses in a mouse model of acute promyelocytic leukemia (APL). This study reports the efficacy of a non-specific DNA vaccine, pVAX14Flipper (pVAX14), in both APL and high risk myelodysplastic syndrome (HR-MDS) models. PVAX14 is comprised of novel immunogenic DNA sequences inserted into the pVAX1 therapeutic plasmid. APL mice treated with pVAX14 combined with ATRA had increased survival comparable to that obtained with a specific PML-RARA vaccine. Moreover, the survival advantage correlated with decreased PML-RARA transcript levels and increase in anti-RARA antibody production. In HR-MDS mice, pVAX14 significantly improved survival and reduced biomarkers of leukemic transformation such as phosphorylated mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) 1. In both preclinical models, pVAX14 vaccine significantly increased interferon gamma (IFNγ) production, memory T-cells (memT), reduced the number of colony forming units (CFU) and increased expression of the adapter molecule signalling to NF-κB, MyD88. These results demonstrate the adjuvant properties of pVAX14 providing thus new approaches to improve clinical outcome in two different models of myeloid malignancies, which may have potential for a broader applicability in other cancers.
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