Visual Universitätsmedizin Mainz

Cancer Immunotherapy

The contributions of UCT 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 members strengthen and promote translational research and provide substantial outreach capacities to pharmaceutical companies and regulatory authorities as well (FZI, Ci3, CIMT). Spinoff companies (Ganymed, BioNTech, TRON) form a hub to translate innovative concepts originating from the UCT research into clinical applications.

Achievements

  • UCT 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 more recently 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).
     
  • Various targets are currently addressed in phase I/II trials (e.g.: therapeutic antibodies for upper gastrointestinal tract and ovarian cancer patients - NCT02054351, NCT01671774, NCT01630083; personalized therapeutic vaccination of melanoma and breast cancer patients: NCT02316457, NCT02035956). Other targets, e.g. MHC-independent targets for T cell receptors (TCRs) (European Patent EP 2932264 A1), currently undergo preclinical evaluation.
     
  • The development of adoptive TCR transfer strategies (M. Theobald) is another long-term followed project of the UCT. 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). Technical advances in TCR cloning aim at individualized TCR applications (Omokoko T. Oncoimmunology 2015). 
     
  • The UCT cancer immunotherapists are strongly linked to the „Drug Delivery and Development“ program. This has led to an ongoing first-in-man study with a lipoplex-encapsulated RNA vaccine (NCT02410733).
     
  • Immune evasion imposes a major hurdle to cancer immunotherapy. Since more than a decade UCT 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 (Bopp T. Cancer Immunol. Immunother. 2010; Muth S. Eur. J. Immunol. 2014; Ulges A. Nat. Immunol. 2015).
     
  • Local research groups working on the immunosuppressive role of regulatory T cells, innate lymphoid cells and myeloid-derived suppressor cells have combined their forces to establish a new collaborative research center initiative (SFBi) for immune interventions targeting inefficient immunity (to be funded by the Deutsche Forschungsgemeinschaft (DFG).

Aims

Our already existing alliances with transregional partners are instrumental in research, clinical studies and regulatory aspects. Newly available tools, such as genome- and transcriptome-wide sequencing (e.g. IVAC MUTANOME), and the discovery of generally valid immune escape mechanisms will support efforts to address a wider range of disease entities, e.g. lung cancer, head-and-neck cancer, sarcomas and malignancies of the central nervous system. 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 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.

Most significant publications since 2013

  • 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.
     
  • Micke, P., J.S. Mattsson, K. Edlund, M. Lohr, K. Jirström, A. Berglund, J. Botling, J..Rahnenfuehrer, M. Marincevic, F. Pontén, S. Ekman, J. Hengstler, S. Wöll, U. Sahin, and O. Türeci. 2014 Aberrantly activated claudin 6 and 18.2 as potential therapy targets in non-small-cell lung cancer. Int J Cancer. 135:2206-2214.
     
  • Britten, C.M., H. Singh-Jasuja, B. Flamion, A. Hoos, C. Huber, K.J. Kallen, S.N. Khleif, S. Kreiter, M. Nielsen, H.G. Rammensee, U. Sahin, T. Hinz, and U. Kalinke. 2013. The regulatory landscape for actively personalized cancer immunotherapies. Nat Biotechnol. 31:880-882.
     
  • Landsberg, J., J. Kohlmeyer, M. Renn, T. Bald, M. Rogava, M. Cron, M. Fatho, V. Lennerz, T. Wolfel, M. Holzel, and T. Tuting. 2012. Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation. Nature. 490:412-416.
     
  • Castle, J.C., S. Kreiter, J. Diekmann, M. Lower, N. Van de Roemer, J. de Graaf, A. Selmi, M. Diken, S. Boegel, C. Paret, M. Koslowski, A.N. Kuhn, C.M. Britten, C. Huber, O. Tuereci, and U. Sahin. 2012. Exploiting the Mutanome for Tumor Vaccination. Cancer Research. 72:1081-1091.

 
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© Dr. Triche, National Cancer Institute