Metastatic breast cancer continues to account for more than 400,000 deaths yearly with HER2 positive breast cancers representing approximately one third of cases. Despite the efficacy of trastuzumab in HER2 overexpressing breast cancer, progression of metastatic disease is inevitable. Lapatinib, when combined with capecitabine, improves time to progression in those with trastuzumab resistant disease, but lapatinib resistance also develops in the majority of these patients. HER2 overexpression is also reported in lung, gastric, ovarian, and pancreatic cancers, all of which are also in need of improved treatment options. Because HER2 continues to be expressed in patients with refractory disease, using an immune-targeting approach against HER2 remains a promising strategy. A number of clinical trials have confirmed the ability of vaccines to activate T cell and antibody responses against HER2. We propose using a propagation-defective, single-cycle, RNA replicon vector system that expresses HER2 as an antigen-specific cancer vaccine in a Phase I clinical trial in patients with advanced or metastatic malignancies expressing HER2. The vaccine was prepared from an attenuated strain of an alphavirus in which 3 of the 7 viral genes were removed and replaced with a HER2 gene to create a self-amplifying RNA (replicon) that expresses large amounts of HER2. The HER2 gene used includes the extracellular domain (ECD) and transmembrane (TM) regions of HER2 but not the ICD region. The HER2 ECDTM replicon is packaged into virus-like replicon particles (VRP) by providing the alphavirus structural proteins from separate RNA molecules. When VRP are used for immunization, the VRP infect individual cells and the replicon expresses HER2 which then induces an immune response.