Targeting the mutanome of HCC by viral inflammation and tumor-directed vaccinations: a model for individualized tumor therapy

• Applicant: Professor Dr. Florian Kühnel
• Subject Area: Gastroenterology ; Immunology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 279621100

Oncolytic virotherapy and immunotherapies promise enormous potential for the treatment of hepatocellular carcinoma (HCC). In previous experiments we have developed an innovative and highly effective immunotherapeutic strategy which facilitates an effective tumor-targeted dendritic cell vaccination during inflammation of the tumor by an oncolytic virus (= oncolysis-assisted DC-vaccination, or ODC). In further preliminary work in a lung cancer cell we established a diagnostic/therapeutic procedure involving identification of the tumor mutanome by whole exome sequencing, followed by in-silico prediction of potentially immunogenic neoepitopes and verification by T cell analyses after intratumoral infection with oncolytic adenoviruses. In the proposed project we want to develop a personalized therapy strategy for the treatment of HCC involving an optimized ODC strategy to elicit strong antitumoral immune response against immunogenic neoepitopes of individual tumor mutanomes. We want to address the therapeutic efficacy of optimized ODC against immunogenic neoepitopes in clinically relevant, transgenic mouse models. First, we want to analyse the spectrum of non-synonymous single nucleotide variants in selected HCC cell lines by whole exome sequencing. After determination of the mutanome, we define promising MHC class I-binding neoepitopes using the SYFPEITHI algorithm. Successful triggering of CD8 T cell responses against immunogenic neoepitopes will be identified by CD8 T cell screens after oncolytic virus infection of subcutaneous tumors in a syngeneic mouse model. In these models, we want to use these immunogenic neoepitopes to define the rules for optimized preparation of DC-vaccines targeting a complete mutanome. Antigen-specific immune responses will be determined by ELISpot analyses and in-vivo cytotoxicity measurements. Therapeutic efficacy will be assessed by monitoring tumor growth, survival, and metastases formation. Finally, we want to investigate the therapeutic potential of corresponding ODC-based vaccine in our novel electroporation model for transgenic intrahepatic HCC. These investigations will provide essential informations for a future clinical trial of personalized immunotherapy of HCC.

• DFG Programme: Research Grants