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.
Highlights
A DNA vaccine is composed of a plasmid DNA that encodes an antigen of interest or an immunogenic sequence [1, 2, 3] DNA-based strategies have emerged as a promising approach to immunotherapy development, they suffer from low immunogenicity which limits their effectiveness; emphasis is www.impactjournals.com/oncotarget on the importance of adjuvants as crucial components of successful vaccines
To assess the efficacy of the pVAX14 vaccine, we first used, as a proof of concept, the acute promyelocytic leukemia (APL) mouse model [13] where we previously identified and documented the enhanced survival induced by the specific vaccine PMLRARA in combination with all-trans retinoic acid (ATRA) compared with either ATRA alone or ATRA+pcDNA3 empty vector [8]
Survival of the APL mice treated by ATRA in combination with the specific PML-RARA as well as with the non-specific pVAX14 was significantly (p < 0.0001 and p < 0.0014, respectively) superior to that of the mice treated by ATRA alone (Figure 1B, Supplementary Table S1)
Summary
A DNA vaccine is composed of a plasmid DNA that encodes an antigen of interest or an immunogenic sequence [1, 2, 3] DNA-based strategies have emerged as a promising approach to immunotherapy development, they suffer from low immunogenicity which limits their effectiveness; emphasis is www.impactjournals.com/oncotarget on the importance of adjuvants as crucial components of successful vaccines. Recent studies have been focused on strategies to improve the immunogenicity of DNA vaccines [4, 5]. Targeted therapies for hematological malignancies have matured since the advent of all-trans retinoic acid (ATRA) to treat acute promyelocytic leukemia (APL) [6]. APL is a specific subtype of acute myeloid leukemia (AML) characterized by the t(15;17) translocation resulting in a PML-RARA (for promyelocytic leukemiaretinoic acid receptor alpha) fusion protein. We demonstrated that a specific PML-RARA DNA vaccine, when combined with ATRA, improved survival over treatment with ATRA alone, with a protective effect that was B and T-cell mediated [7, 8, 9]
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