Immunogenicity, tumor rejection potential and safety of MUC1 cancer vaccines in transgenic mouse models

We addressed questions related to CD4+ T cell tolerance in the MUC1 transgenic model wherein human MUC1 is a self antigen. In particular, we examined the immunogenicity and tumor rejection potential of MUC1 peptide based vaccines in MUC1 Tg. versus WT mice. We also investigated whether tumor rejection responses elicited resulted in autoimmune destruction of MUC1-expressing tissues. Injection of MUC1 peptide admixed with adjuvants such GM-CSF or SB-AS2 elicited humoral responses that differed between wild type and MUC1 Tg. The IgG responses elicited by the MUM peptide+SB-AS2 vaccine were induced by cytokines produced by non-T cells. MUC1 Tg. mice immunized with peptide-pulsed DC or biodegradable MUC1 peptide-loaded microspheres both developed MUC1 specific CD8+ T cell responses. Although the DC vaccine was unable to elicit MUC1-specific CD4+ T cell responses in MUC1 Tg. mice, it induced tumor rejection responses comparable to those seen in wild type mice. Our most exciting result was that the MUC1 PLGA microsphere vaccine could overcome CD4+ T cell tolerance in the absence of adjuvant. Tumor rejection in exciting result was that the MUC1 PLGA microsphere vaccine could overcome CD4+ T cell tolerance in the absence of adjuvant.; These results suggest that different vaccination protocols have different capabilities of eliciting MUC1 specific antibody or T cell mediated responses in MUC1 Tg. mice. Potent MUC1-specific CD4+ or CD8+ T cell or anti-tumor responses do not result in autoimmunity in the MUC1 Tg, mouse model. Our observations in the HLA-A11/MUC1 double Tg. mouse model suggest that peptide-pulsed DC elicit tumor rejection responses in the absence of observable autoimmunity. However, this immunization protocol did not appear to be very effective in the elicitation of HLA-A11 restricted T cells. This work has set the stage for further experiments designed to determine the efficacy and safety of HLA-A11 restricted MUC1-specific CTL responses. (Abstract shortened by UMI.)...