Insertion of the DNA for the 163–171 peptide of IL1β enables a DNA vaccine encoding p185neu to inhibit mammary carcinogenesis in Her-2/neu transgenic BALB/c mice

Abstract

An assessment was made of the effectiveness of DNA vaccination in prevention of the mammary adenocarcinomas of BALB/c female mice transgenic for the activated rat Her-2/neu oncogene. Atypical hyperplasia is evident in their mammary glands when they are 6 weeks old and in situ carcinoma by the 13th week. Palpable invasive carcinomas appear around the 17th week and are always evident in all 10 glands by the 33rd week. Intramuscular vaccinations with 100 g plasmid DNA encoding the extracellular domain of the Her-2/neu p185 (ECD) performed at the 6th, 12th, 18th and 24th week provided no significant protection, whereas those ECD plasmids in which the DNA coding for the

Venezuelan Equine Encephalitis Replicon Immunization Overcomes Intrinsic Tolerance and Elicits Effective Anti-tumor Immunity to the ‘Self’ tumor-associated antigen, neu in a Rat Mammary Tumor Model

“…These results were obtained in a rat tumor model that has expression of the TAA in an entirely physiologic manner in contrast to the various rat neu transgenic mouse models [43][44][45][46][47][48][49][50][51][52][53][54][55][56][57] and using a designed TAA target antigen selected to enhance both specificity and elicited Th1/ cytotoxic T lymphocyte (CTL) immune responses. The failure of immunization with VRPs expressing an irrelevant antigen, HA, to protect animals from tumor challenge strongly supports the generation of antigen-specific anti-tumor immune responses.…”

“…In contrast, the highly conserved rat homologue rat neu, both wild type and mutated/activated (tumorigenic) sequences, has been well characterized. Transgenic mouse models using both wild type and activated rat neu have been developed and have been useful in studies of anti-tumor immunotherapies including those targeting neu [43][44][45][46][47][48][49][50][51][52][53][54][55][56][57]. It is widely acknowledged that expression of transgene encoded products can result in immunologic tolerance [47] however, the expression pattern is not always consistent with normal physiology.…”

HER-2/neu-gene engineered dendritic cell vaccine stimulates stronger HER-2/neu-specific immune responses compared to DNA vaccination

“…9 The antitumor immune responses induced by DNA vaccines could protect mice from challenge of HER-2/neu-positive tumor cells 10,11 and partially reduce tumor development in rat HER-2/neu-gene transgenic mice. [12][13][14] Insertion of interleukin (IL)-1b sequence 15 or co-administration of genetic adjuvants 16,17 or primeboost vaccination with plasmid DNA and adenovirus gene therapy 18 all induced enhanced antitumor immunity. However, these approaches still did not induce any therapeutic effects even with in vivo DNA electroporations.…”

HER2 peptide-specific CD8+ T cells are proportionally detectable long after multiple DNA vaccinations

“…Extensive analyses of DNA vaccination targeting HER2/neu have been reported by the use of transgenic mice with either activated rat neu gene [17][18][19][20][21] or over expressing wild-type neu gene. 22,23 Investigators aimed to examine whether DNA vaccination of plasmids of cognate cDNA may break immunological tolerance against HER2/neu-derived peptides in those transgenic mice.…”

“…Some investigators claim the possible involvement of T cell-mediated immunity, 17,21 while others stress the role of antibodies. 19,20 Since HER2/neu is expressed in a variety of normal murine tissues and also in some limited normal adult human tissues, difficulty inducing effective in vivo anti-HER2 immune responses leading to tumor destruction is still conceivable. Our previous reports on preventive, as well as therapeutic in vivo tumor suppression by immunization with defined peptides derived from murine HER2 gene 9,11 are in agreement with multiple analyses of HER2/neu transgenic mice and may provide a strong rationale setting HER2/neu molecules as targets of active immunotherapy.…”