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Immunization of cancer patients with HER-2/neu-derived peptides demonstrating high-affinity binding to multiple class
Lupe G Salazar1, John Fikes, Scott Southwood
1Tumor Vaccine Group, Division of Oncology, University of Washington, Seattle, Washington, USA. lsalazar@u.washington.edu
Purpose:
The purpose of this study was to immunize patients with HER-2/neu-overexpressing cancer with a multipeptide vaccine comprised of four class II HER-2/neu peptides that had been identified as the most immunogenic in a previous clinical trial. Furthermore, we questioned whether MHC binding affinity could predict the in vivo immunogenicity of the HER-2/neu helper peptides.
Experimental Design:
Four putative class II HER-2/neu peptides, which were found to generate detectable specific T-cell responses (stimulation index > 2) in a majority of patients in a previous study, were used to formulate a single vaccine. The multipeptide vaccine was administered intradermally with granulocyte macrophage colony-stimulating factor as an adjuvant. Ten patients with HER-2/neu overexpressing breast or lung cancer were enrolled. HER-2/neu peptide-and protein-specific T cell and antibody immune responses were measured. Competitive inhibition assays were used to analyze the class II HER-2/neu peptides for their binding affinity to 14 common HLA-DR alleles.
Results:
Twenty-five percent of patients developed HER-2/neu peptide-specific T-cell immunity, and 50% developed HER-2/neu peptide-specific antibody immunity. No patient developed HER-2/neu protein-specific T cell or antibody immunity. The majority of peptides exhibited high binding affinity, in vitro, to >/==" BORDER="0">3 of the 14 DR alleles analyzed.
Conclusion:
The group of peptides used in this study demonstrated high binding affinity to multiple DR alleles suggesting that in vitro binding affinity may be able to predict the in vivo immunogenicity of class II peptides. However, only a minority of patients immunized with the multipeptide vaccine developed HER-2/neu peptide-specific T cell or antibody immunity, and none developed HER-2/neu protein-specific immunity.
Insights
This study investigated a HER-2/neu multipeptide vaccine for cancer patients. While peptides showed high binding affinity, only a minority developed immunity, highlighting challenges in predicting in vivo immunogenicity.
Area of Science:
- Oncology
- Immunology
- Vaccine Development
Background:
- HER-2/neu overexpression is common in breast and lung cancers.
- Previous trials identified immunogenic HER-2/neu peptides.
- Predicting peptide immunogenicity in vivo remains a challenge.
Purpose of the Study:
- To immunize patients with HER-2/neu-overexpressing cancer using a multipeptide vaccine.
- To assess if MHC binding affinity predicts in vivo immunogenicity of HER-2/neu helper peptides.
Main Methods:
- A vaccine composed of four class II HER-2/neu peptides was administered intradermally with GM-CSF adjuvant.
- Immune responses (T cell and antibody) to HER-2/neu peptides and protein were measured in 10 patients.
- In vitro binding affinity of peptides to 14 HLA-DR alleles was analyzed.
Main Results:
- 25% of patients developed HER-2/neu peptide-specific T-cell immunity; 50% developed antibody immunity.
- No patients developed HER-2/neu protein-specific immunity.
- Most peptides demonstrated high in vitro binding affinity to multiple HLA-DR alleles.
Conclusions:
- High in vitro binding affinity suggests potential for predicting in vivo immunogenicity of class II peptides.
- The multipeptide vaccine elicited limited peptide-specific immunity in a minority of patients.
- No protein-specific immunity was observed, indicating limitations of this vaccine approach.
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