The development of a successful cancer vaccine requires the ability to break immunological tolerance to self-Ags expressed on tumor cells. The transgenic rat insulin promoter (RIP) OVA(LOW) mouse model has been reported to be hyporesponsive for both OVA-specific CD4 and CD8 T cell responses. The experiments described in the current study show that this hyporesponsiveness can be overcome by inclusion of GM-CSF and the TLR7 agonist imiquimod as adjuvants in a DNA immunization regimen with OVA-encoding plasmids. High frequencies of OVA-specific CD8 and CD4 T cells, including a response to a CD4 T cell epitope seen only in the RIP OVA(LOW) mice, were generated by this regimen. These responses were associated with the development of autoimmunity and increased protection to tumor challenge in the RIP OVA(LOW) mice. Heterologous CD4 T cell help has been shown to improve functional CD8 T cell responses, and we confirmed that inclusion of the CD4 T cell epitope pan HLA-DR-binding epitope improved CD8 T cell responses compared with self-Ag alone. Addition of GM-CSF and imiquimod, however, resulted in dominance of the pan HLA-DR-binding epitope-specific response over the OVA-specific CD4 T cell responses, decreased OVA-specific CD8 T cell numbers and function in tolerant RIP OVA(LOW) mice, and failure to induce diabetes. The results of this study suggest that the use of heterologous help needs to be evaluated carefully in the context of specific immunization regimes and that a preferable approach may be adjuvantization of DNA vaccines.