DNA immunization using constant-current electroporation affords long-term protection from autochthonous mammary carcinomas in cancer-prone transgenic mice

Abstract

A recently developed, adaptive constant-current electroporation technique was used to immunize mice with an intramuscular injection of plasmid coding for the extracellular and transmembrane domains of the product of the rat neu 664V-E oncogene protein.In wild-type BALB/c mice, plasmid electroporation at lower current settings elicits higher antibody titers, a strong cytotoxic response and completely protects all mice vaccinated with 10, 25 and 50 mg of plasmid against a lethal challenge of rat neu þ carcinoma cells. BALB/c mice transgenic for the transforming rat neu 664VÀE (ErbB-2, Her-2/neu) oncogene (BALB-neuT 664VÀE ) develop an invasive mammary gland carcinoma by 20 weeks of age. Remarkably, when transgenic BALB-neuT 664VÀE mice were vaccinated at a 10-week interval with 50 mg of plasmid with 0.2 A electroporation, mice remained tumor free for more than a year. A single administration of plasmid associated with electroporation was enough to markedly delay carcinogenesis progression in mice with multiple microscopic invasive carcinomas, and keep about 50% of mice tumor free at one year of age. Thus, vaccination using a clinically relevant dose of plasmid encoding the extracellular and transmembrane domains of the neu oncogene delivered by electroporation prevents long-term tumor formation. These improvements in the efficacy of this cancer vaccine regimen vastly increase its chances for clinical success.

Erbb2 DNA Vaccine Combined with Regulatory T Cell Deletion Enhances Antibody Response and Reveals Latent Low-Avidity T Cells: Potential and Limits of Its Therapeutic Efficacy

“…During the lengthy stepwise progression of their mammary lesions, T reg cells expand to bring about rampant immunosuppression (19). When the lesions are initial and the tumor-elicited suppression is still negligible, the protection provided by anti-rErbb2 vaccines prevents their progression and persists for almost as long as the natural life span of wild-type BALB/c mice (14,22), whereas their efficacy dramatically fades if these initial lesions have progressed, and is almost null against diffuse invasive microscopic tumors (14,22,23,30).…”

Attenuation of PI3K/Akt-Mediated Tumorigenic Signals through PTEN Activation by DNA Vaccine-Induced Anti-ErbB2 Antibodies

“…In these mice, DNA vaccination elicits anti-rat ErbB2 Abs and a T cell-dependent cytotoxicity (40). To evaluate whether EC-TM neu vaccination induces a protective response on established tumors, BALB/c mice bearing 2-mm-mean diameter TUBO carcinomas (∼10 d after TUBO cell challenge) were electroporated with EC-TM neu or control pcDNA3 plasmids.…”

Induction of humoral and cellular immune responses by antigen-expressing immunostimulatory liposomes

“…This indicates that mainly the amounts of protein antigen determine the strength of antibody responses and that the DNA vaccine did not play any role in the induction of humoral immunity. Normally, to induce a robust immune response, a DNA vaccine needs adjuvants and/or strong in vivo DNA transfection [12][13][14][15][16]. Non-adjuvanted liposomal DNA failed to induce any humoral responses in mice whereas mice vaccinated with electroporated pDNA most probably had enough endogenous antigen production to induce reasonable antibody responses (Fig.…”