HER-2/neu is a tumor rejection target in tolerized HER-2/neu transgenic mice

HER-2/neu (neu-N) transgenic mice, which express the nontransforming rat pr oto-oncogene, develop spontaneous focal mammary adenocarcinomas beginning a t 5-6 months of age, The development and histology of these tumors bears a striking resemblance to what is seen in patients with breast cancer. We hav e characterized the immunological responses to HER-2/neu (neu) in this anim al model. neu-positive tumor lines, which were derived from spontaneous tum ors that formed in neu-N animals, are highly immunogenic in parental, FVB/N mice. In contrast, a 100-fold lower tumor challenge is sufficient for grow th in 100% of transgenic animals. Despite significant tolerance to the tran sgene, neu-specific immune responses similar to those observed in breast ca ncer patients can be demonstrated in neu-N mice prior to vaccination. Both cellular and humoral neu-specific responses In transgenic mice can be boost ed with neu-specific vaccination, although to a significantly lesser degree than what is observed in FVB/N mice, indicating that the T cells involved are less responsive than in the nontoleragenic parental strain, Using irrad iated whole-cell and recombinant vaccinia virus vaccinations we are able to protect neu-N mice from a neu-expressing tumor challenge. T-cell depletion experiments demonstrated that the observed protection is T cell dependent. The vaccine-dependent neu-specific immune response is also sufficient to d elay the onset of spontaneous tumor formation in these mice. These data sug gest that, despite tolerance to neu in this transgenic model, it Is possibl e to immunize neu-specific T cells to achieve neu-specific tumor rejection in vivo. These transgenic mice provide a spontaneous tumor model for identi fying vaccine approaches potent enough to overcome mechanisms of immune tol erance that are likely to exist in patients with cancer.