Oncotarget

Research Papers: Immunology:

DNA-mediated adjuvant immunotherapy extends survival in two different mouse models of myeloid malignancies

Carole Le Pogam, Satyananda Patel, Petra Gorombei, Laura Guerenne, Patricia Krief, Nader Omidvar, Nilgun Tekin, Elena Bernasconi, Flore Sicre, Marie-Helene Schlageter, Martine Chopin, Maria-Elena Noguera, Robert West, Ansu Abu, Vikram Mathews, Marika Pla, Pierre Fenaux, Christine Chomienne and Rose Ann Padua _

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Oncotarget. 2015; 6:32494-32508. https://doi.org/10.18632/oncotarget.5572

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Abstract

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

Correspondence to:

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

Abstract

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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