Imiquimod and S-27609 as adjuvants of DNA vaccination in a transgenic murine model of HER2/neu-positive mammary carcinoma

Abstract

DNA vaccination against HER-2/neu is an effective way to induce an immune response able to oppose the spontaneous development of mammary tumours occurring in HER-2/neu transgenic mice. In this study, we have evaluated the potential of Imiquimod and the analogue S-27609 as adjuvants of DNA vaccination against HER-2/neu in transgenic mice. The association of a DNA vaccine encoding a portion of rat HER2/neu with either Imiquimod or S-27609 was found to delay the development of spontaneous mammary tumours and to reduce their incidence, in comparison with DNA vaccination alone. Almost 80 or 40% of tumour-free mice were found at the end of measurement time in mice vaccinated and supplemented with Imiquimod or S-27609, respectively. The antitumour preventive effect was associated with increased antibody and cell-mediated immune responsiveness against HER-2/neu. In mice vaccinated and supplemented with Imiquimod, a small but significant increase of rat p185 neu -specific cytotoxicity and of IFN-g and IL-2-producing CD8T cells, together with a reduction of IL-4-producing CD4T cells, and a switch from an IgG1 towards a IgG2a phenotype of anti-p185 neu antibodies, suggested a TH1 polarization of the immune response. The immunoregulatory efficacy of S-27609 was lower than that observed for Imiquimod. These data highlight the potential of Imiquimod, and, to a lower extent, of S-27609, as immunological adjuvants of therapeutic DNA vaccines.

Aluminium hydroxide potentiates a protective Th1 biased immune response against polio virus that allows for dose sparing in mice and rats

“…Similar observations were made with the CAF01 adjuvant in a recent study using the mouse model [14]. As polio virus is a positive stranded RNA virus it can most probably trigger Toll-like receptor 7 and 8 [37] which has been shown to lead to a Th1 polarization of the immune response characterized by elevated expression of Th1 cytokines and a switch from an IgG1 towards a IgG2a isotype in the mouse [38][39][40][41]. Interestingly, triggering of Toll receptor 7/8 by adding Resiquimod (known to bind TLR 7/8) to Aluminium hydroxide also leads to a Th1 dominated immune response ( Supplementary Fig.…”

Resiquimod and other immune response modifiers as vaccine adjuvants

“…Resiquimod also acted as a modest vaccine adjuvant when given to mice that were immunized with a DNA vaccine for HIV-1 Gag protein [64]. When administered along with a DNA vaccine to HER-2/neu, imiquimod enhanced the antitumor response to spontaneous tumor formation in a genetically engineered mouse model of breast cancer and this was associated with increased antibody-and cell-mediated immune response [65]. Since DNA vaccines have had limited benefit clinically, IRMs or other adjuvants may be necessary for demonstration of efficacy.…”

The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy

“…injection of imidazoquinolines also resulted in protective antitumor immune responses in a transgenic mouse model of mammary carcinoma, in which the plasmid encoding the TAA was administered by a gene gun method [61].…”