Forschung

Mutation-derived tumor neoepitopes

Summary of the Project

Although cancer therapy has improved substantially over the last decades, there is still a high need for more specific anti-cancer treatments. Cancer immunotherapies may be a solution to this challenge.

Checkpoint blockade agents have mediated impressive tumor regressions – however, as these agents act unspecifically on all activated T cells, severe autoimmune reactions also have been observed. 

The beneficial responses triggered by these therapies have been found mostly to be directed against tumor mutation derived neoepitopes. Thus, therapies specifically targeting these epitopes, such as neoepitope-specific vaccinations or adoptive transfer of neoepitope-specific T cells, could combine the efficiency of existing immunotherapeutic approaches with tumor-specificity. 

To achieve this, it is crucial to identify neoepitopes which are presented to the immune system on the surface of tumor cells, and are therefore suitable targets.

Scientific Goals

  • Assess the presence (and thus targetability) of tumor-specific neoepitopes on the tumor cell surface by mass spectrometry. 
  • Explore the capacity of the identified neoepitopes to stimulate tumor-reactive T cells. 
  • Open the possibility of developing future therapies against such validated epitopes.
Neoepitopes

Josef K, Klevenz, A, Vormehr M, Diken M, Kreiter S, Sahin U, Blatnik R, Riemer AB. Direct detection of predicted tumor neoepitopes by targeted mass spectrometry. EMBL-Cancer Core Europe Conference on Cancer Immunotherapy, Plenary Talk, February 2017.

Volkmar M, Rebmann J, Hotz-Wagenblatt A, Poschke I, Espinosa O, Offringa R. Identification of neoepitopes from PDAC xenograft exomes using a hybrid reference genome. EMBL-Cancer Core Europe Conference on Cancer Immunotherapy, Oral presentation, February 2017.

Tunger A, Wehner R, von Bonin M, Kühn D, Heidenreich F, Matko S, Nauerth M, Rücker-Braun E, Dietz S, Link CS, Eugster A, Odendahl M, Busch DH, Tonn T, Bonifacio E, Germeroth L, Schetelig J, Bachmann MP, Bornhäuser M, Schmitz M. Generation of high-avidity, WT1-reactive CD8+ cytotoxic T cell clones with anti-leukemic activity by streptamer technology. Leuk Lymphoma 2017, 58(5): 1246-9.

Koşaloğlu Z, Zörnig I, Halama N, Kaiser I, Buchhalter I, Grabe N, Eils R, Schlesner M, Califano A, Jäger D. Identification of immunotherapeutic targets by genomic profiling of rectal NET metastases. Oncoimmunology 2016, 5(11):e1213931.

Schumacher T, Bunse L, Pusch S, Sahm F, Wiestler B, Quandt J, Menn O, Osswald M, Oezen I, Ott M, Keil M, Balß J, Rauschenbach K, Grabowska AK, Vogler I, Diekmann J, Trautwein N, Eichmüller SB, Okun J, Stevanović S, Riemer AB, Sahin U, Friese MA, Beckhove P, von Deimling A, Wick W, Platten M. A vaccine targeting mutant IDH1 induces antitumor immunity. Nature 2014, 512(7514): 324-7.