Microsphere-based immunotherapy of hepatocellular carcinoma

• Applicant: Privatdozent Dr. Thomas Wirth
• Subject Area: Gastroenterology ; Clinical Immunology and Allergology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 561188803

Hepatocellular carcinoma is one of the most common cancers worldwide and is associated with a high mortality rate. In recent years, immunotherapy has established itself as a new therapeutic pillar in everyday clinical practice, whereas vaccines have not yet been approved despite clear evidence of therapeutic activity. As part of our research project, we will further develop the heterologous costimulatory T-cell vaccines developed and patented by us, which are currently based on peptide immunizations, into highly effective LNP/mRNA vaccines and simultaneously optimize the affinity of the previously established HLA-A2 specific HCC antigens Glypican-3 and AFP. As we were able to show in our preliminary work, the immunogenicity of conventional, commercial LNP/mRNA vaccines can be further enhanced by the additional use of mRNA coding for costimulatory agonistic molecules. We would like to pursue this approach consistently in order to further increase the immunogenicity and therapeutic efficacy of the vaccines and have this protected as a patent. We will use HLA-A2-specific epitopes as antigens, which we will heteroclitically optimize in their affinity to HLA-A2 by mutation in anchor positions of the epitopes, as we have already been able to achieve for other antigens. We will test the combination of the improved LNP/mRNA vaccine and the affinity-optimized HLA-A2 epitopes in HLA-A2 transgenic mice in an autochthonous HCC model. As a third improvement approach, we will combine these vaccines with anti-VEGF and/or anti-PD1 antibodies. We hope that this improvement of conventional T-cell vaccination will lead to a significant advance in therapeutic efficacy and an important step towards translation into the clinic.

• DFG Programme: Research Grants