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: 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, Rose Ann Padua
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 32 Pg. 32494-508 (Oct 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26378812 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adjuvants, Immunologic
• Antibodies
• Cancer Vaccines
• Rara protein, mouse
• Receptors, Retinoic Acid
• Retinoic Acid Receptor alpha
• Vaccines, DNA
• Tretinoin
• Interferon-gamma

Topics

• Adjuvants, Immunologic (pharmacology)
• Animals
• Antibodies (blood)
• Base Sequence
• Cancer Vaccines (immunology, pharmacology)
• Gene Expression Regulation, Neoplastic
• Genes, ras
• Immunologic Memory (drug effects)
• Interferon-gamma (immunology, metabolism)
• Leukemia, Promyelocytic, Acute (drug therapy, genetics, immunology, metabolism, pathology)
• Lymphocytes, Tumor-Infiltrating (drug effects, immunology, metabolism)
• Mice, Transgenic
• Molecular Sequence Data
• Myelodysplastic Syndromes (drug therapy, genetics, immunology, metabolism, pathology)
• Neoplasms, Experimental (drug therapy, genetics, immunology, metabolism, pathology)
• Receptors, Retinoic Acid (genetics, metabolism)
• Retinoic Acid Receptor alpha
• Signal Transduction (drug effects)
• T-Lymphocytes (drug effects, immunology, metabolism)
• Time Factors
• Tretinoin (pharmacology)
• Tumor Burden (drug effects)
• Vaccination
• Vaccines, DNA (immunology, pharmacology)