HER-2 overexpression is observed in approximately 25% of all breast cancers and is associated with poorer overall survival and decreased time to relapse. Target therapies directed against HER-2 have been developed and used clinically, but many patients continue to develop resistance. Breast cancer is immunogenic and well suited to treatment via immunomodulation. HSP90 is a chaperon for most of the important signal transduction system in HER-2 type breast cancer; HER-2, ER / PR and Akt, the downstream protein of PI3K. Therefore, HSP90 is considered as a potential therapeutic target in order to improved treatment of HER-2 positive resistant breast cancer. Immunotherapy targeting HSP90 has been tried before, however, no clinically available vaccine due to limitation of autologous cell-based approach. We questioned whether HSP90 was an immune target in HER-2 positive breast cancer. First, HSP90-specific IgG antibody immunity was detected in the sera from HER-2 positive breast cancer patients. Next, potential MHC class II epitopes derived from HSP90 with high binding affinity across multiple human HLA genotypes were identified using in silico algorithms. Top 11 peptides were synthesized and Th1 vs Th2 immunity were assessed in human PBMCs. After IFN-γ and IL-10 ELISPOT assays, epitopes inducing Th1-directed immunity were selected for in vivo experiments. Immunogenecity of HSP90 peptides vaccine was evaluated in FVB mice model and showed strong antigen-specific T cell responses in IFN-γ ELISPOT assay. Then, we assessed the anti-tumor effect of immunization with HSP90 peptides vaccine in MMTV-neu-transgenic mouse model after autologous cancer cell implantation. Peptides vaccines derived from HSP90 significantly inhibited tumor growth compared with control group (mean ± SD; 1896 ± 1211 mm3 vs. mean ± SD; 774 ± 136 mm3, respectively; p < 0.05). The tumor-inhibitory effect was associated with HSP90 peptide-specific IFN-γ-secreting T cell responses in immunization group. Also, immunohistochemical staining of tumors derived from immunized mice was performed to examine immune microenvironment and the protein expression of HER-2 pathways. Taken together, multi-epitope peptides vaccine derived from HSP90 is immunogenic in breast cancer patients and is a promising tumor antigen. Based on efficacies in tumor-rejection in vivo, further research in combination with immune modulating antibodies will be performed in the lapatinib-resistant tumor model.
Citation Format: Jinho Kang. The development to peptide vaccine targeting heat shock protein 90 to overcome resistance to HER-2 target drugs in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5635.