Therapeutic DNA vaccination against XXXX by targeting the @entity17227 oncoprotein.

@entity1707 @entity17227 @entity5 @entity19 @entity786 @entity1961 @entity14 @entity116
Cancers can be addicted to continued and relatively high expression of nuclear oncoproteins. This is evident in @entity14 ( @entity14 ) where the oncoprotein and transcription factor @entity17227 is over expressed and essential to continued proliferation and @entity5 cell survival. Historically, targeting transcription factors in the context of @entity5 has been very challenging. Nevertheless, we formulated a DNA vaccine to generate a @entity17227 -specific immune response in the belief @entity17227 peptides might be aberrantly presented on the cell surface of @entity14 cells. @entity17227 , like many @entity5 antigens, is weakly immunogenic as it is a 'self' antigen and is subject to tolerance. To break tolerance, a fusion vaccine was generated comprising a full-length @entity17227 complementary DNA (cDNA) flanked by two potent @entity1961 -epitopes derived from @entity116 toxoid. Vaccination was achieved against @entity5 initiated by two distinct highly aggressive, syngeneic @entity5 cell lines (CT26 and MC38) that express @entity17227 . This was done in BALB/c and C57BL/6 @entity19 strains respectively. We introduced multiple inactivating mutations into the oncogene sequence for safety and sub-cloned the cDNA into a Food and Drug Administration (FDA)-compliant vector. We used low dose @entity786 (CY) to overcome T-regulatory cell immune suppression, and anti-program cell death receptor 1 (anti- @entity1707 ) antibodies to block T-cell exhaustion. Anti-PD-1 administered alone slightly delayed @entity5 growth in MC38 and more effectively in CT26 bearing @entity19 , while CY treatment alone did not. We found that therapeutic vaccination elicits protection when MC38 @entity5 burden is low, mounts @entity5 -specific cell killing and affords enhanced protection when MC38 and CT26 @entity5 burden is higher but only in combination with anti-PD-1 antibody or low dose CY, respectively.
