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Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based
Mary L Disis1, Theodore A Gooley, Kristine Rinn
1Division of Oncology and Department of Dermatology, University of Washington, Seattle 98195-6527, USA. ndisis@u.washington.edu
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.
Insights
This study shows that HER-2/neu peptide vaccines can generate T-cell immunity in patients with HER-2/neu-overexpressing cancers. This immunity, linked to epitope spreading, can persist long-term, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Immunology
- Vaccine Development
Background:
- HER-2/neu protein is overexpressed in various cancers like breast and ovarian cancer.
- Tumor antigens, including self-proteins, necessitate strategies to overcome immune tolerance for effective vaccines.
- Subdominant peptide epitopes are explored for their potential to elicit T-cell responses against tumor antigens.
Purpose of the Study:
- To investigate if immunizing patients with HER-2/neu-derived peptide epitopes using granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjuvant can generate T-cell immunity.
- To assess the ability of peptide-based vaccines to circumvent tolerance against self-proteins like HER-2/neu.
- To evaluate the generation of antigen-specific T-cell immunity in patients with HER-2/neu-overexpressing malignancies.
Main Methods:
- Sixty-four patients with HER-2/neu-overexpressing breast, ovarian, or non-small-cell lung cancer were enrolled.
- Vaccines consisted of HER-2/neu peptide epitopes mixed with GM-CSF, administered intradermally.
- Peripheral blood mononuclear cells were analyzed for T-cell immunity before and after vaccination; 38 patients completed six vaccinations.
Main Results:
- 92% of patients developed T-cell immunity to HER-2/neu peptides, and 68% to the HER-2/neu protein domain.
- Epitope spreading, indicating an endogenous immune response, was observed in 84% of patients and correlated with protein-specific immunity (P=.03).
- Immunity to the HER-2/neu protein persisted in 38% of patients at the 1-year follow-up.
Conclusions:
- Most patients with HER-2/neu-overexpressing cancers can develop immunity to both HER-2/neu peptides and the protein.
- Peptide immunization can induce protein-specific immunity through epitope spreading, activating an endogenous immune response.
- The generated immunity can be sustained even after the cessation of active immunization.
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