title: DNA-mediated adjuvant immunotherapy extends survival in two different mouse models of myeloid malignancies.
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.
authors.affiliation: Unité Mixte de la Recherche de Santé (UMR-S), Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U), Paris, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Le Pogam
authors.affiliation: Unité Mixte de la Recherche de Santé (UMR-S), Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U), Paris, France.
authors.forename: Satyananda
authors.initials: S
authors.lastname: Patel
authors.affiliation: Unité Mixte de la Recherche de Santé (UMR-S), Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U), Paris, France.
authors.forename: Petra
authors.initials: P
authors.lastname: Gorombei
authors.affiliation: Unité Mixte de la Recherche de Santé (UMR-S), Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U), Paris, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Guerenne
authors.affiliation: Unité Mixte de la Recherche de Santé (UMR-S), Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U), Paris, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Krief
authors.affiliation: Haemotology Department, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Nader
authors.initials: N
authors.lastname: Omidvar
authors.affiliation: Biotechnology Institute, Ankara University, Ankara, Turkey.
authors.forename: Nilgun
authors.initials: N
authors.lastname: Tekin
authors.affiliation: Unité Mixte de la Recherche de Santé (UMR-S), Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U), Paris, France.
authors.forename: Elena
authors.initials: E
authors.lastname: Bernasconi
authors.affiliation: Unité Mixte de la Recherche de Santé (UMR-S), Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U), Paris, France.|Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Flore
authors.initials: F
authors.lastname: Sicre
authors.affiliation: Unité Mixte de la Recherche de Santé (UMR-S), Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U), Paris, France.|Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Marie-Helene
authors.initials: MH
authors.lastname: Schlageter
authors.affiliation: Département d'Expérimentation Animale, Institut Universitaire d'Hématologie, University Paris Diderot, Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Chopin
authors.affiliation: Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Maria-Elena
authors.initials: ME
authors.lastname: Noguera
authors.affiliation: Welsh Heart Research Institute, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: West
authors.affiliation: Department of Hematology, Christian Medical College and Hospital, Vellore, India.
authors.forename: Ansu
authors.initials: A
authors.lastname: Abu
authors.affiliation: Department of Hematology, Christian Medical College and Hospital, Vellore, India.
authors.forename: Vikram
authors.initials: V
authors.lastname: Mathews
authors.affiliation: Unité Mixte de la Recherche de Santé (UMR-S), Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U), Paris, France.
authors.forename: Marika
authors.initials: M
authors.lastname: Pla
authors.affiliation: Unité Mixte de la Recherche de Santé (UMR-S), Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U), Paris, France.|Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fenaux
authors.affiliation: Unité Mixte de la Recherche de Santé (UMR-S), Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U), Paris, France.|Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Chomienne
authors.affiliation: Unité Mixte de la Recherche de Santé (UMR-S), Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U), Paris, France.|Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Rose Ann
authors.initials: RA
authors.lastname: Padua
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies / Q000097:blood; D001483:Base Sequence; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D007156:Immunologic Memory / Q000187:drug effects; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology / Q000494:pharmacology*
chemical_list: D000276:Adjuvants, Immunologic; D000906:Antibodies; D019496:Cancer Vaccines; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D019444:Vaccines, DNA; D014212:Tretinoin; D007371:Interferon-gamma
keywords: APL; Immune response; Immunity; Immunology and Microbiology Section; MDS; memory T-cells; plasmid DNA based immunotherapy