Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines

Mary L. Disis, Theodore A. Gooley, Kristine Rinn, Donna Davis, Michael Piepkorn, Martin A. Cheever, Keith L. Knutson, Kathy Schiffman

Research output: Contribution to journalArticle

365 Scopus citations

Abstract

Purpose: The HER-2/neu protein is a nonmutated tumor antigen that is overexpressed in a variety of human malignancies, including breast and ovarian cancer. Many tumor antigens, such as MAGE and gp100, are self-proteins; therefore, effective vaccine strategies must circumvent tolerance. We hypothesized that immunizing patients with subdominant peptide epitopes derived from HER-2/neu, using an adjuvant known to recruit professional antigen-presenting cells, granulocyte-macrophage colony-stimulating factor, would result in the generation of T-cell immunity specific for the HER-2/neu protein. Patients and Methods: Sixty-four patients with HER-2/neu-overexpressing breast, ovarian, or non-small-cell lung cancers were enrolled. Vaccines were composed of peptides derived from potential T-helper epitopes of the HER-2/neu protein admixed with granulocyte-macrophage colony-stimulating factor and administered intradermally. Peripheral-blood mononuclear cells were evaluated at baseline, before vaccination, and after vaccination for antigen-specific T-cell immunity. Immunologic response data are presented on the 38 subjects who completed six vaccinations. Toxicity data are presented on all 64 patients enrolled. Results: Ninety-two percent of patients developed T-cell immunity to HER-2/neu peptides (stimulation index, 2.1 to 59) and 68% to a HER-2/neu protein domain (stimulation index range, 2 to 31). Epitope spreading was observed in 84% of patients and significantly correlated with the generation of a HER-2/neu protein-specific T-cell immunity (P = .03). At 1-year follow-up, immunity to the HER-2/neu protein persisted in 38% of patients. Conclusion: The majority of patients with HER-2/ neu-overexpressing cancers can develop immunity to both HER-2/neu peptides and protein. In addition, the generation of protein-specific immunity, after peptide immunization, was associated with epitope spreading, reflecting the initiation of an endogenous immune response. Finally, immunity can persist after active immunizations have ended.

Original languageEnglish (US)
Pages (from-to)2624-2632
Number of pages9
JournalJournal of Clinical Oncology
Volume20
Issue number11
DOIs
StatePublished - Jun 1 2002

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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