Visual Universitätsmedizin Mainz

Cancer Immunotherapy

The contributions of UCT Mainz members to tumor immunology and cancer immunotherapy emanated from a four-decade-long investment in immunology. Activities range from excellent basic to translational research with early interventional trials. Immunotherapy represents a key translational research focus within the UCT Mainz and the entire Medical Faculty. Local, regional, national as well international collaboration platforms initiated by UCT Mainz members strengthen and promote translational research and provide substantial outreach capacities to pharmaceutical companies and regulatory authorities as well (FZI, Ci3, CIMT). Spinoff companies (BioNTech, TRON) form a hub to translate innovative concepts originating from the UCT Mainz research into clinical applications.

Achievements

  • UCT Mainz members developed a tradition of target identification via computational data mining, SEREX (Ö. Türeci, U. Sahin), mass spectrometry (H. Schild, S. Tenzer), T cell-based expression cloning (T. Wölfel) and Next Generation Sequencing (NGS) to systematically exploit the mutanome for individualized immunotherapy (Castle J.C. Cancer Res. 2012; Kreiter S. Nature 2015; Pritchard A.L. Cancer Immunol. Res. 2015; Kranz LM. Nature 2016). Since 2016, this project was purposively further developed by TRON and finally addressed in first-in-human clinical trials in melanoma (Sahin U., et al. Nature 2017, NCT02035956) and tripple negative breast cancer (TNBC-MERIT, NCT02316457).
  • Feasibility of individualized immunogenic RNA vaccines for widespread use just in time is currently addressed in a phase I/II basket trial in patients with solid Tumors (NCT03289962).
  • Novel routes of application of individualized immunotherapy have been developed by TRON e.g. lipoplex-encapsulated RNA vaccines (NCT02410733) or intranodal injection of naked RNA (NCT01684241).
  • Novel preclinical developments include targeting of tumors by mRNA-encoded bispecific antibodies (Stadler CR., et al. Nat Med. 2017) or improvement of mRNA-based therapeutic gene delivery (Orlandini von Niessen AG., et al. Mol Ther. 2019).
  • The development of adoptive TCR transfer strategies (M. Theobald) is another long-term followed project of the UCT Mainz. Avoidance of mispairing and avidity enhancement went along with the generation of new structural formats (Voss R.H. Blood 2010; Thomas S. Eur. J. Immunol. 2012) and resulted in the development of a high-affinity p53-single-chain-TCR for TCR-based immunotherapy (Echchannaoui H., Mol Ther. 2019).
  • Engineering of universal epitope-specific chimeric antigen receptor (UniCAR)-modified natural killer cells off-the-shelf is addressed in the DKTK joint funding project "UniCAR NK cells” and identification of MHC-independent targets for TCRs (T. Wölfel) currently undergoes preclinical evaluation.
  • Immune evasion imposes a major hurdle to cancer immunotherapy. Since more than a decade UCT Mainz researchers (e.g. E. Schmitt, H. Jonuleit, T. Bopp, H.C. Probst, H. Schild) have continuously contributed seminal work on molecular mechanisms influencing T cell regulation and leading to T cell tolerance. Currents efforts include the analysis of cell intrinsic mechanisms (Ulges A., et al. Nat. Immunol. 2015), the microenvironment (Bohn T., et al. Nat Immunol. 2018), amino acid metabolism (Werner A., et al. Front Immunol. 2017) or interaction with coagulation factors (Graf C., et al. Sci Immunol. 2019).
  • Local research groups working on the immunosuppressive role of regulatory T cells, innate lymphoid cells and myeloid-derived suppressor cells have combined their forces and established the DFG-funded CRC1292 "Targeting convergent mechanisms of inefficient immunity in tumors and chronic infections".

Aims

To meet the challenges of multifaceted immune escape mechanisms mounted in the course of tumor-host interactions and by tumor plasticity, the cancer immunotherapy program of the UCT Mainz will encourage and support the development of combined modality approaches, e.g. target-specific immunotherapy together with checkpoint blockade, irradiation and/or signal transduction inhibition, and will foster the design of precision immunotherapy regimes involving diverse mechanisms of tumor recognition. In addition, we will establish a UCT Mainz-wide (re)biopsy program linked to an Immune Oncology Board to support translational research and innovative treatment strategies.

Working Groups

Department of Internal Medicine III - Hematology, Oncology and Pneumology:

Department of Dermatology:

BiomaTiCS:  

Institute of Immunology:

Institute of Translational Immunology:

Intitute of Molecular Medicine:

TRON:

Most significant publications since 2015

  • Türeci O, Sahin U, Schulze-Bergkamen H, Zvirbule Z, Lordick F, Koeberle D, Thuss-Patience P, Ettrich T, Arnold D, Bassermann F, Al-Batran SE, Wiechen K, Dhaene K, Maurus D, Glod M, Huber C, Krivoshik A, Arozullah A, Park JW, Schuler M. 2019. A multicentre, phase 2a study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study. Ann Oncol. 30(9):1487-1495.
  • Graf C, Wilgenbus P, Pagel S, Pott J, Marini F, Reyda S, Kitano M, Macher-Göppinger S, Weiler H, Ruf W. 2019. Myeloid cell-synthesized coagulation factor X dampens antitumor immunity. Science immunology. 4(39).
  • Vascotto F, Petschenka J, Walzer KC, Vormehr M, Brkic M, Strobl S, Rösemann R, Diken M, Kreiter S, Türeci Ö, Sahin U. 2019. Intravenous delivery of the toll-like receptor 7 agonist SC1 confers tumor control by inducing a CD8+ T cell response. Oncoimmunology. 8, 1601480.
  • Orlandini von Niessen AG, Poleganov MA, Rechner C, Plaschke A, Kranz LM, Fesser S, Diken M, Löwer M, Vallazza B, Beissert T, Bukur V, Kuhn AN, Türeci Ö, Sahin U. 2019. Improving mRNA-Based Therapeutic Gene Delivery by Expression-Augmenting 3' UTRs Identified by Cellular Library Screening. Mol Ther. 27(4):824-836.
  • Hilf N, Kuttruff-Coqui S, Frenzel K, Bukur V, Stevanovic S, Gouttefangeas C, Platten M, Tabatabai G, Dutoit V, van der Burg SH, Thor Straten P, Martinez-Ricarte F, Ponsati B, Okada H, Lassen U, Admon A, Ottensmeier CH, Ulges A, Kreiter S, von Deimling A, Skardelly M, Migliorini D, Kroep JR, Idorn M, Rodon J, Piró J, Poulsen HS, Shraibman B, McCann K, Mendrzyk R, Löwer M, Stieglbauer M, Britten CM, Capper D, Welters MJP, Sahuquillo J, Kiesel K, Derhovanessian E, Rusch E, Bunse L, Song C, Heesch S, Wagner C, Kemmer-Brück A, Ludwig J, Castle JC, Schoor O, Tadmor AD, Green E, Fritsche J, Meyer M, Pawlowski N, Dorner S, Hoffgaard F, Rössler B, Maurer D, Weinschenk T, Reinhardt C, Huber C, Rammensee HG, Singh-Jasuja H, Sahin U, Dietrich PY, Wick W. 2019. Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature. 565(7738): 240-245.
  • Bohn T, Rapp S, Luther N, Klein M, Bruehl TJ, Kojima N, Aranda Lopez P, Hahlbrock J, Muth S, Endo S, Pektor S, Brand A, Renner K, Popp V, Gerlach K, Vogel D, Lueckel C, Arnold-Schild D, Pouyssegur J, Kreutz M, Huber M, Koenig J, Weigmann B, Probst HC, von Stebut E, Becker C, Schild H, Schmitt E, Bopp T. 2018. Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nat Immunol. 19(12):1319-1329.
  • Buehler U, Schulenburg K, Yurugi H, Šolman M, Abankwa D, Ulges A, Tenzer S, Bopp T, Thiede B, Zipp F, Rajalingam K. 2018. Targeting prohibitins at the cell surface prevents Th17-mediated autoimmunity. EMBO J. 37 (16).
  • Sahin U, Derhovanessian E, Miller M, Kloke BP, Simon P, Löwer M, Bukur V, Tadmor AD, Luxemburger U, Schrörs B, Omokoko T, Vormehr M, Albrecht C, Paruzynski A, Kuhn AN, Buck J, Heesch S, Schreeb KH, Müller F, Ortseifer I, Vogler I, Godehardt E, Attig S, Rae R, Breitkreuz A, Tolliver C, Suchan M, Martic G, Hohberger A, Sorn P, Diekmann J, Ciesla J, Waksmann O, Brück AK, Witt M, Zillgen M, Rothermel A, Kasemann B, Langer D, Bolte S, Diken M, Kreiter S, Nemecek R, Gebhardt C, Grabbe S, Höller C, Utikal J, Huber C, Loquai C, Türeci Ö. 2017. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature. 547(7662):222-226.
  • Stadler CR, Bähr-Mahmud H, Celik L, Hebich B, Roth AS, Roth RP, Karikó K, Türeci Ö, Sahin U. 2017. Elimination of large tumors in mice by mRNA-encoded bispecific antibodies. Nature Medicine. 23(7):815-817.
  • Frick SU, Domogalla MP, Baier G, Wurm FR, Mailänder V, Landfester K, Steinbrink K. 2016. Interleukin-2 Functionalized Nanocapsules for T Cell-Based Immunotherapy. ACS Nano. 10(10):9216-9226.
  • Kranz LM, Diken M, Haas H, Kreiter S, Loquai C, Reuter KC, Meng M, Fritz D, Vascotto F, Hefesha H, Grunwitz C, Vormehr M, Hüsemann Y, Selmi A, Kuhn AN, Buck J, Derhovanessian E, Rae R, Attig S, Diekmann J, Jabulowsky RA, Heesch S, Hassel J, Langguth P, Grabbe S, Huber C, Türeci Ö, Sahin U. 2016. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature. 534(7607):396-401.
  • Kreiter, S., M. Vormehr, N. van de Roemer, M. Diken, M. Lower, J. Diekmann, S. Boegel, B. Schrors, F. Vascotto, J.C. Castle, A.D. Tadmor, S.P. Schoenberger, C. Huber, O. Tureci, and U. Sahin. 2015. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature. 520:692-U269. 
     
  • Ulges, A., M. Klein, S. Reuter, B. Gerlitzki, M. Hoffmann, N. Grebe, V. Staudt, N. Stergiou, T. Bohn, T.J. Bruhl, S. Muth, H. Yurugi, K. Rajalingam, I. Bellinghausen, A. Tuettenberg, S. Hahn, S. Reissig, I. Haben, F. Zipp, A. Waisman, H.C. Probst, A. Beilhack, T. Buchou, O. Filhol-Cochet, B. Boldyreff, M. Breloer, H. Jonuleit, H. Schild, E. Schmitt, and T. Bopp. 2015. Protein kinase CK2 enables regulatory T cells to suppress excessive T(H)2 responses in vivo. Nature Immunology. 16:267-U227.