Activation of tumor-reactive T lymphocytes is a promising approach for the prevention and treatment of patients with metastatic cancers. Strategies that activate CD8(+) T cells are particularly promising because of the cytotoxicity and specificity of CD8(+) T cells for tumor cells. Optimal CD8(+) T cell activity requires the co-activation of CD4(+) T cells, which are critical for immune memory and protection against latent metastatic disease. Therefore, we are developing "MHC II" vaccines that activate tumor-reactive CD4(+) T cells. MHC II vaccines are MHC class I(+) tumor cells that are transduced with costimulatory molecules and MHC II alleles syngeneic to the prospective recipient. Because the vaccine cells do not express the MHC II-associated invariant chain (Ii), we hypothesized that they will present endogenously synthesized tumor peptides that are not presented by professional Ii(+) antigen presenting cells (APC) and will therefore overcome tolerance to activate CD4(+) T cells. We now report that MHC II vaccines prepared from human MCF10 mammary carcinoma cells are more efficient than Ii(+) APC for priming and boosting Type 1 CD4(+) T cells. MHC II vaccines consistently induce greater expansion of CD4(+) T cells which secrete more IFNgamma and they activate an overlapping, but distinct repertoire of CD4(+) T cells as measured by T cell receptor Vbeta usage, compared to Ii(+) APC. Therefore, the absence of Ii facilitates a robust CD4(+) T cell response that includes the presentation of peptides that are presented by traditional APC, as well as peptides that are uniquely presented by the Ii(-) vaccine cells.