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C06: Targeting the mutanome of liver cancer by viral oncolysis and tumor-directed immunotherapies

Viroimmunotherapy is an innovative therapy that has shown first successful therapeutic results in advanced melanoma but failed to improve overall survival in a phase IIb study in HCC. We have shown in previous work that oncolytic viruses induce inflammation of the tumor tissue and cross-presentation of tumor antigens providing excellent preconditions for immunotherapies such as immune checkpoint blockade. To investigate neoepitope-specific CD8 T-cell responses upon virotherapy and pharmacologic inhibition of the PD-1/PD-L1 axis, we have determined the neoepitope spectrum by transcriptomic sequencing and epitope prediction in CMT64 lung cancer cells. In s.c. implanted syngeneic tumors we showed that localized virotherapy with simultaneous blockade of the PD-1/PD-L1 axis using a PD-1-antagonistic antibody, led to a strong epitope-spreading of CD8 T-cell responses associated with improved immune-mediated elimination of lung metastases demonstrating that viral oncolysis overcomes systemic tumor resistance to PD-1/PD-L1 immunotherapy. Importantly, therapeutic efficacy of virotherapy and PD-1/PD-L1 checkpoint blockade was confirmed in a transgenic liver tumor model with spontaneous lung metastasis. In this project, we will investigate epitope spreading in response to oncolytic virotherapy and PD-1/PD-L1 checkpoint inhibition in mouse models with subcutaneously grown tumors of established murine HCC cell lines or self-generated HCC cell lines expressing a predefined CD4 and CD8 T-cell neoepitope spectrum. Furthermore, we will investigate the patterns of neoepitope-specific T-cell responses triggered by different oncolytic viruses (adenovirus, measles, vaccinia virus) and the influence of different immunostimulatory transgenes in epitope spreading. These investigations are urgently required to develop suitable immunotherapeutic strategies using virotherapy and immune checkpoint inhibition for liver cancers.


a) Peer-reviewed articles and books
• Kendre G, Marhenke S, Lorz G, Kühnel F, Woller N, Reineke-Plaaß T, Poth T, Becker D, Marquardt JU, Wirtz RM, Bonin M, Saborowski M, Vogel A*, Saborowski A* (2021). The co-mutational spectrum determines the therapeutic response in murine FGFR2 fusion - driven cholangiocarcinoma. Hepatology. doi: 10.1002/hep.31799. *equal contribution.
• 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.
• Mishra A, Emamgholi F, Erlangga Z, Hartleben B, Unger K, Wolff K, Teichmann U, Kessel M, Woller N, Kühnel F, Dow LE, Manns MP, Vogel A, Lowe SW, Saborowski A, Saborowski M (2020) Generation of focal mutations and large genomic deletions in the pancreas using inducible in vivo genome editing. Carcinogenesis 41:334-344.
• 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.
• Erlangga Z, Wolff K, Poth T, Peltzer A, Nahnsen S, Spielberg S, Timrott K, Woller N, Kühnel F, Manns MP, Saborowski A, Vogel A, Saborowski M (2019) Potent antitumor activity of liposomal irinotecan in an organoid- and CRISPR-Cas9-based murine model of gallbladder cancer. Cancers 11:1904.
• Brooks J, Fleischmann-Mundt B, Woller N, Niemann J, Ribback S, Peters K, Demir IE, Armbrecht N, Ceyhan GO, Manns MP, Wirth TC, Kubicka S, Bernhardt G, Smyth MJ, Calvisi DF, Gürlevik E, Kühnel F (2018) Perioperative, spatiotemporally coordinated activation of T and NK cells prevents recurrence of pancreatic cancer. Cancer Res 78:475-488.
b) Other publications, both peer-reviewed and non-peer-reviewed
• Niemann J, Kühnel F (2020) Tumor targeting of oncolytic adenoviruses using bispecific adapter proteins. Methods Mol Biol 2058:31-49.
• Peter M, Kühnel F (2020) Oncolytic adenovirus in cancer immunotherapy. Cancers 12:3354
• Martin NT, Wrede C, Niemann J, Brooks J, Schwarzer D, Kühnel F*, Gerardy-Schahn R* (2018) Targeting polysialic acid-abundant cancers using oncolytic adenoviruses with fibers fused to active bacteriophage borne endosialidase. Biomaterials 158:86-94, *equal contribution.
• Wirth TC, Kühnel F (2017) Neoantigen targeting-dawn of a new era in cancer immunotherapy? Front Immunol 8:1848.
• Ungerechts G, Engeland CE, Buchholz CJ, Eberle J, Fechner H, Geletneky K, Holm PS, Kreppel F, Kühnel F, Lang KS, Leber MF, Marchini A, Moehler M, Mühlebach MD, Rommelaere J, Springfeld C, Lauer UM, Nettelbeck DM (2017) Virotherapy research in Germany: from engineering to translation. Hum Gene Ther 28:800-819.