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C05: Microsphere-based immunotherapy of HCC

Hepatocellular carcinoma is increasingly recognized as an immunogenic tumor that represents a promising target for immunotherapy. In recent clinical trials, checkpoint blockade has induced durable remissions in a subset of patients treated with anti-PD-1 antibodies and currently the therapeutic value of both PD-1 and PD-L1 targeted immunotherapy is evaluated in clinical trials. The success of targeted vaccines, however, has so far been disappointing due to the immunosuppressive liver micromilieu which prevents induction of efficacious adaptive immune responses. We have established a prime-boost vaccination based on a primary immunization with antigen-coated polylactic co-glycolic acid (PLGA) microspheres and a secondary infection with Listeria monocytogenes (LM), a vector that does not induce humoral immunity in humans. Compared to conventional vaccines consisting of homologous immunizations of a combination of the target antigen with adjuvants, PLGA-LM vaccinations are by far more potent and induce cytolytic CD8 T cell immune responses in less than 14 days. The aim of the research proposal is to develop novel, heterologous PLGA/LM prime-boost vaccinations for the treatment of hepatocellular carcinoma and to test our therapeutic vaccination in the context of an orthotopic liver cancer model. To this extent, we will target glypican-3, a GPI-anchored surface protein that is frequently overexpressed in HCC and incorporate the target antigen into Listeria monocytogenes vectors. Using the orthotopic murine liver cancer model, we will furthermore aim at identifying suppressors of CD8 T cell function in the context of a Listeria-based vaccine. For this purpose we have performed Listeria vaccinations in mice bearing advanced, diffuse HCC and isolated exhausted HCC-specific CD8 T cells from the tumor-bearing mice. From these T cells we were able to assess the first whole genome transcriptomic signature of HCCspecific exhausted T cells and comparative mRNA expression profiles from naive and functional effectors CD8 T cells. For the research project proposed, we will make use of these unique microarray profiles to identify novel regulators of T cell exhaustion that could be exploited for therapeutic purposes. Furthermore, we will screen for surface markers on HCC-specific T cells that allow for the identification of tumorspecific T cells in peripheral blood samples without a priori knowledge of their cognate antigen.


a) Peer-reviewed articles and books
• Ostroumov D, Duong S, Wingerath J, Woller N, Manns MP, Timrott K, Kleine M, Ramackers W, Roessler S, Nahnsen S, Czemmel S, Dittrich-Breiholz O, Eggert T, Kühnel F, Wirth TC (2020) Transcriptome profiling identifies TIGIT as a marker of T cell exhaustion in liver cancer. Hepatology. doi: 10.1002/hep.31466.
• Niemann J, Woller N, Brooks J, Fleischmann-Mundt B, Martin NT, Kloos A, Knocke S, Ernst AM, Manns MP, Kubicka S, Wirth TC, Gerardy-Schahn R, Kühnel F (2019) Molecular retargeting of antibodies converts immune defense against oncolytic viruses into cancer immunotherapy. Nat Commun 10:3236.
• Owusu Sekyere S, Schlevogt B, Mettke F, Kabbani M, Deterding K, Wirth TC, Vogel A, Manns MP, Falk CS, Cornberg M, Wedemeyer H (2019) HCC Immune surveillance and antiviral therapy of Hepatitis C virus infection. Liver Cancer 8:41-65.
b) Other publications, both peer-reviewed and non-peer-reviewed
• Kirstein MM, Wirth TC (2020) Multimodal treatment of hepatocellular carcinoma. Internist (Berl) 61:164-169.
• de Knegt RJ, Potthoff A, Wirth TH (2020) Management of benign liver tumors. Internist (Berl) 61:140-146.
• Wirth TC, Niemann J, Kühnel F (2020) Live vaccines-a short-cut to cancer viro-immunotherapy. EMBO Mol Med 12:e11496.
• Wingerath J, Ostroumov D, Woller N, Manns MP, Pinschewer DD, Orlinger K, Berka U, Kühnel F, Wirth TC (2017) Recombinant LCMV vectors induce protective immunity following homologous and heterologous vaccinations. Mol Ther 25:2533-2545.
• Wirth TC, Kühnel F (2017) Neoantigen Targeting-Dawn of a New Era in Cancer Immunotherapy? Front Immunol 8:1848.