HER2+ breast cancer (HER2+ BC) is an aggressive type of breast cancer that claims the lives of over 120,000 women annually worldwide. Current treatments for HER2+ BC rely on chemotherapy in combination with trastuzumab, pertuzumab, and trastuzumab-emtansine (TD-M1), which target the HER2 receptor on cancer cells. While initially responsive to these treatments, HER2+ breast cancer eventually progress.. Beyond these therapies there are limited options recognized to have a significant clinical benefit with therapies such as Lapatinib (a chemotherapy drug) demonstrating a benefit in time to progression, but not in overall survival. Although these therapies have resulted in higher response rates, longer time to progression and increased survival in some patients with metastatic disease, they are plagued by drug-related toxicities that have long- term adverse effects that severely impact the quality of life of patients. Considering these limitations, HER2+ BC poses a major clinical challenge, and developing new agents that are effective and safe is a critical unmet need. Veana Therapeutics has developed a novel proprietary clinical drug candidate, a-TEA-Lysine (a-TEA- Lys) that kills cancer but not normal cells in a fashion that stimulates anti-tumor immunity. In pre-clinical studies, we demonstrated that a-TEA-Lys is safe and efficacious in causing regression of established HER2/neu-expressing tumors. Veana has conducted a first-in-human dose escalation trial of a-TEA-Lys in patients with multiple types of advanced cancer. At the doses tested, a-TEA-Lys was safe, well tolerated and stopped tumor from growing (stable disease) in 12 of 17 patients (70%). The safety profile of a-TEA-Lys, coupled with its pro-apoptotic and immune-stimulating properties, make it an ideal candidate to combine with HER2-specific antibody to eliminate tumors. The goal of this application is to conduct proof-of-concept pre- clinical studies to determine the optimum dosing schedule of a-TEA and anti-HER2/neu combination therapy that will yield the best therapeutic outcome while limiting toxicity. We will pursue three specific aims to achieve this goal: Aim 1: Determine the schedule of a-TEA-Lys/anti-HER2/neu combination therapy that will elicit lasting tumor regression in a well-described pre-clinical model of HER2/neu+ breast cancer. Aim 2: Identify surrogate immunologic biomarkers of effective a-TEA-Lys/anti-HER2/neu combination therapy. Aim 3: Compare the antitumor activity and toxicity profile of a-TEA/anti-HER2/neu treatment with that of paclitaxel/anti-HER2/neu and lapatinib/anti-HER2/neu treatments. We will assess tumor growth and survival, and perform hematological analysis, complete necropsy and examination of tissues and organs of treated animals. Completion of the studies and realization of the milestones will lay the groundwork for a Phase II grant application to evaluate safety and tolerability of a-TEA plus trastuzumab in a first-in-human combination trial in pati...