Breast cancer (BrCa) occurs in 1 of 9 women. The strongest predictor of recurrent disease is the number of tumor positive axillary nodes at diagnosis. Women with 4-10 positive lymph nodes have a 70 percent chance of recurrence within 10 years and women with 11-20 positive nodes have an 82 percent chance of recurrence within ten years. New non-toxic strategies are needed to improve overall survival and progression free- survival. Since HER2/neu (HER2) is over expressed in BrCa, HER2 is ideal target for anti-CD3 activated T cells (ATC) """"""""armed"""""""" with bispecific antibodies (BiAb) which bind to CD3 on T cells and HER2 protein on tumor cells to augment specific cytotoxicity. Our preliminary studies show that ATC from normal subjects and cancer patients can be expanded after anti-CD3 activation in low dose IL-2 and then armed with chemically heteroconjugated anti- CD3 x anti-HER2 (Her2Bi). The armed ATC are highly cytotoxic to HER2+ MCF-7 and SK-BR-3 cell lines at effector to target ratios as low as 3:1. This phase I/II trial using immunotherapy (IT) consisting of multiple infusions of Her2Bi armed ATC, IL-2, and GM-CSF will involve women with HER2 positive and negative biopsies.
The aims of this proposal are: 1) Perform a phase I dose-escalation clinical trial in women with stable, HER2/neu positive or HER2/neu negative stage IV breast cancer with measurable or evaluable disease, in order to determine the maximum tolerated dose (MTD) for HER2Bi-armed ATC given in combination with IL-2 and GM-CSF. Each patient will receive 8 infusions (twice a week for 4 weeks) with dose levels of 2.5, 5, 10, 20, and 40 x 109 HER2Bi-armed ATC or until the dose is technically limiting. Fifteen to 30 patients are needed for the phase I; 2) Perform a phase II study using the MTD determined in Aim 1 in 33 women with stable, measurable or evaluable stage IV breast cancer and whose tumors demonstrate 2+ or 3+ HER2/neu overexpression to define the toxicity profile at the MTD, evaluate clinical responses; and to estimate overall and progression free survival; 3) Evaluate in vivo/in vitro clinical parameters in the phase I and II studies to develop in vitro correleates of clinical events by: a) monitoring serum HER2/neu receptors (sHER2r), CA27-29, carcinoembryonic antigen (CEA) and antibody responses to mouse proteins (HAMA); and b) sequentially monitoring immune responses to evaluate immune modulation induced by IT; and 4) Determine if HER2Bi armed-ATC traffic to metastatic tumor sites in selected HER2/neu positive patients who have evaluable or measurable disease. The studies will provide immunologic insights as to whether armed ATC can alter the immune systems of patients with both HER2+.
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