In this proposal, the applicants propose to use a multiantigen preventive vaccine (TNBCvax) that simultaneously targets multiple tumor antigens (TOP2A, IGF-IR, and HIF-1α) in order to effectively overcome antigen-negative variant escape. Individually, TOP2A, IGF-IR, and HIF-1α are overexpressed in triple-negative breast cancer (TNBC). Each single-antigen vaccine has shown significant efficacy in a mouse model of TNBC in a primary prevention setting. The applicants hypothesize that their novel major histocompatibility complex (MHC) II-restricted TNBCvax multiantigen vaccine will be more effective than individual-antigen vaccines in preventing TNBC in mice carrying existing early lesions, and that TNBCvax will induce a potent T-cell memory response to prevent secondary tumor cell challenges. The long-term goal is to generate strong preclinical data to support the clinical use of TNBCvax. The most relevant trial design will be to prevent tumor progression in patients with TNBC premalignant lesions or to prevent metastasis in subjects with primary malignant lesions where there is no evidence of recurrence.