Originally published as JCO Early Release 10.1200/JCO.2008.20.6789 on August 31 2009

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Concurrent Trastuzumab and HER2/neu-Specific Vaccination in Patients With Metastatic Breast Cancer

From the Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington; Fred Hutchinson Cancer Research Center, Seattle, WA; and Breastlink Medical Group, Long Beach, CA.

Corresponding author: Mary L. Disis, MD, Tumor Vaccine Group, Center for Translational Medicine in Women's Health, 815 Mercer St, 2nd Floor, Box 358050, University of Washington, Seattle, WA 98195-8050; e-mail: ndisis{at}u.washington.edu.

Purpose The primary objectives of this phase I/II study were to evaluate the safety and immunogenicity of combination therapy consisting of concurrent trastuzumab and human epidermal growth factor receptor 2 (HER2)/neu-specific vaccination in patients with HER2/neu-overexpressing metastatic breast cancer.

Patients and Methods Twenty-two patients with stage IV HER2/neu-positive breast cancer receiving trastuzumab therapy were vaccinated with an HER2/neu T-helper peptide-based vaccine. Toxicity was graded according to National Cancer Institute criteria, and antigen specific T-cell immunity was assessed by interferon gamma enzyme-linked immunosorbent spot assay. Data on progression-free and overall survival were collected.

Results Concurrent trastuzumab and HER2/neu vaccinations were well tolerated, with 15% of patients experiencing an asymptomatic decline in left ventricular ejection fraction below the normal range during combination therapy. Although many patients had pre-existing immunity specific for HER2/neu and other breast cancer antigens while treated with trastuzumab alone, that immunity could be significantly boosted and maintained with vaccination. Epitope spreading within HER2/neu and to additional tumor-related proteins was stimulated by immunization, and the magnitude of the T-cell response generated was significantly inversely correlated with serum transforming growth factor beta levels. At a median follow-up of 36 months from the first vaccine, the median overall survival in the study population has not been reached.

Conclusion Combination therapy with trastuzumab and a HER2/neu vaccine is associated with minimal toxicity and results in prolonged, robust, antigen-specific immune responses in treated patients.

Supported by grants from Gateway Foundation (Cancer Research Treatment Foundation; M.L.D.) and National Institutes of Health (NIH) Grant No. K23CA100691 (to L.G.S.). Patient care was conducted through the Clinical Research Center Facility at the University of Washington (NIH Grant No. UL1 RR025014).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical Trials repository link available on JCO.org.

Clinical trial information can be found for the following: NCT00194714 [ClinicalTrials.gov] .

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