Background: The recent approval by the FDA of the autologous, cell-based vaccine Provenge was hailed as a major advance for the treatment of advanced prostate cancer (PCa) and reinvigorated interest in the field of PCa immunotherapy. Peptide-based vaccines represent a viable, cost-effective formulation in the field of cancer vaccine development. This approach has been used successfully to treat melanoma where vaccination with gp100-derived peptide in combination with IL-2 gave a 6.7 month improvement in overall survival compared to IL-2 alone. Objectives: Our goal was to identify immunogenic epitopes from gene rearrangement products and tumor coding mutations to generate vaccines for prostate cancer immunotherapy. Methods: We used a 3-step, in silico/in vitro/in vivo approach to identify HLA-A2.1-restricted, immunogenic epitopes derived from the highly prostate tumor-specific antigen ERG, a component of the TMPRSS2:ERG gene fusion that occurs in about 50% of PCa cases. We designed longer epitopes that exhibit helper function through activation of CD4 T lymphocytes. We screened RNAseq data from prostate tumors to identify potential immunogenic epitopes that rise from coding mutations. Predicted epitopes are tested in humanized mice for immunogenicity. Anti-tumor effect of epitope-specific cytotoxic lymphocytes is tested against human prostate tumor cell lines. Results: We have identified several epitopes from ERG that induced a strong immune response in humanized HLA-A2.1+ mice and overcame peripheral tolerance in prostate specific ERG-expressing TRAMP-HLA-A2.1-ERG+ mice. Additionally, we have designed long peptides that target both MHC-I and MHC-II molecules and overcome the need for helper peptides. These immunogenic epitopes are naturally processed and presented by tumor cells to mediate cytotoxicity. Finally, we used RNAseq to identify a high number of tumor-specific, panHLA-customized, coding mutations, including those from KRas oncogene, that exhibit immunogenicity in vivo. Conclusion: Our findings provide proof of concept for peptide-based vaccines that are tailored to the tumor's molecular profile, and lay the ground for future development of personalized vaccines for clinical use.


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