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

Pogam, Carole Le, Patell, Satyananda, Gorombei, Petra, Guerenne, Laura, Krief, Patricia, Omidvar, Nader, Tekin, Nilgun, Bernasconi, Elena, Sicre, Flore, Schlageter, Marie-Helene, Chopin, Martine, Noguera, Maria-Elena, West, Robert, Abu, Ansu, Mathews, Vikram, Pla, Marika, Fenaux, Pierre, Chomienne, Christine and Padua, Rose Ann 2015. DNA-mediated adjuvant immunotherapy extends survival in two different mouse models of myeloid malignancies. Oncotarget 6 (32) , pp. 32494-32508. 10.18632/oncotarget.5572

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General) R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords:	plasmid DNA based immunotherapy, MDS, APL, memory T-cells, Immunology and Microbiology Section, Immune response, Immunity
Publisher:	Impact Journals LLC
ISSN:	1949-2553
Date of Acceptance:	14 August 2015
Last Modified:	13 Jun 2019 09:50
URI:	https://orca.cardiff.ac.uk/id/eprint/85863

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