Cellular immune parameters associated with improved long-term survival in advanced stage breast cancer patients after active immunization with a HER2-specific vaccine

Abstract

3015 Background: Clinical trials of HER2 vaccines have demonstrated that breast cancer patients can be immunized against HER2 and HER2-specific T cells persist long after vaccination. Immunization with HER2 vaccines is associated with the development of epitope spreading; a broadening of immunity to epitopes throughout the HER2 protein. We evaluated the clinical impact of vaccine induced HER2 specific cellular immunity in breast cancer patients immunized with HER2 vaccines. Methods: 75 subjects from 3 phase I-II vaccine trials were analyzed. T cell responses to HER2 peptides, intracellular (ICD) protein and tetanus toxoid (TT) were assessed by tritiated thymadine incorporation. Subjects were included in the analysis if they had complete baseline labs and received at least three vaccinations. Any SI >2.0 was considered positive. Epitope spreading was defined as a positive post-vaccination response to a non-vaccinating peptide. In addition, the relationship between T cell response and overall survival (OS) was assessed (n=50). Patients were followed a median of 2.7 years. Results: There was a significant difference in level of HER2 ICD immunity after vaccination between stages. There were also significant differences in peptide specific SI (p=0.034) and presence of epitope spreading (p=0.006) between stages. HER2 peptide-specific SI was a significant predictor of epitope spreading (p=0.031). Subjects with epitope spreading had significantly higher peptide responses (mean SI: 11.5) than subjects without epitope spreading (mean SI: 3.3) (p<0.001). Univariate analysis demonstrated patients with epitope spreading had longer OS than patients without epitope spreading (p=0.029, HR=0.50), and increased HER2, but not TT, specific T cell immunity, was associated with improved survival (p=0.025, HR=0.94). Multivariate analysis indicated that HER2, but not TT, specific T cell immunity, was an independent variable (p=0.021, HR=0.86) for prediction of OS in advanced stage subjects. Conclusions: These data suggest that vaccine-induced HER2 specific cellular immune response, with epitope spreading, may have clinical benefit and should be further evaluated in the context of phase II studies. No significant financial relationships to disclose.