Background: Anti-CD3 x anti-Her2 bispecific antibody (Her2Bi) retargeting transforms activated T cells (ATC) into non-restricted MHC specific cytotoxic T cells. This study reports a phase I immunotherapy trial beginning in 2001 (NCT00027807) in 23 women with Her2 0-3+ metastatic breast cancer consisting of 8 infusions of HER2Bi armed ATC (aATC) in combination with interleukin 2 (IL-2) and granulocyte-macrophage-colony stimulating factor to evaluate safety, feasibility, time to progression, median overall survival (OS), T cell trafficking and immune responses. Methods: ATC were expanded in IL-2 after anti-CD3 stimulation of mononuclear cells obtained from leukapheresis. Groups of 3 patients (pts) received 5, 10, 20, or 40 x 10e9 aATC per infusion. Results: Total episodes of Grade III-IV side effects for 23pts in decreasing order were chills, headache, nausea/vomiting, back pain, hypertension, and death of 1 pt from congestive heart failure due to digoxin toxicity. aATC persisted in the blood for a week or more and trafficked to tumors. Twelve out of 22 (54.5%) had stable disease (SD) or better. OS was 36.2 months (m) for all pts, 57.4 m for Her2 3+ pts (n=7), and 27.4 m for Her2 0-2+ pts (n=16) with a median follow-up of 36.2 m. For pts with SD, the OS was 57.9 m in the HER2 3+ pts (n=4) and 40 m in the HER2 0-2+ pts (n=7). For pts with progressive disease (PD), OS was 36.6 m in the Her2 3+ pts (n=3) and 21.3 m in the Her2 0-2+ pts (n=9). There was 1 partial response. aATC infusions induced anti-tumor cytotoxicity that persisted >4 m, Th1 cytokines, and increases in IL-12 after 2 weeks. Phenotyping, imaging of In labeled aATC, and tumor biopsies show that aATC circulate > 96 hrs, localize and persist in tumors. Conclusions: aATC infusions are safe with manageable side effects. The OS of 36.2 m is encouraging in heavily pretreated pts. Targeting HER2 positive and negative tumors with aATC induced anti-tumor responses, increased Th1 cytokines, and IL-12 serum levels. The clinical responses suggest that aATC infusions may provide a survival benefit in pts with both stable and progressive disease. These results provide the rationale for conducting phase II trials. Clinical trial information: NCT00027807.