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Research

Neurology

The main research focus of the Department of Neurology is the control of the autoimmunity of the central nervous system and immunotherapeutic approaches for patients with brain tumors, such as glioblastoma.

In recent years, we have uncovered key events in the metabolism of the essential amino acid tryptophan as an endogenous mechanism for inhibiting immune responses in the context of brain tumors and subsequently identified the arylhydrocarbon receptor (AHR) as a key receptor for immunosuppressive endogenous tryptophan metabolites. As part of a collaborative project with Bayer pharmacologic, AHR inhibitors have been identified and are expected to be investigated in a first phase-I clinical study for the treatment of cancer with the aim of strengthening the body‘s antitumor immunity in 2019.

Another line of research is focused on the discovery of new target antigens for the immunotherapy of one type of brain tumor, gliomas. In preclinical models, the immunogenicity of key glioma-specific mutations has already been demonstrated. Based on the work detecting the immunogenicity of the driver mutation IDH1R132H (Bunse, Schumacher, Sahm et al., JCI 2015; Schumacher, Bunse et al., Nature 2014), the multicenter NOA-16 study was completed, which demonstrated the safety and immunogenicity of an IDH1R132H-specific peptide vaccine in patients with gliomas. The DKTK-funded multicenter NOA-21 study has now been initiated to analyze whether the concomitant administration of the checkpoint inhibitor Avelumab results in the amplification of vaccine-induced immune responses and which intratumoral resistance mechanisms determine the effectiveness of this immunotherapeutic approach. With the detection of the immunosuppressive effects of the oncometabolite 2-hydroxyglutarat in preclinical models and tumor tissue, first hypotheses have already been generated (Bunse, Bunse, Pusch et al., Nat Med 2018). In subsequent projects, additional glioma-specific neoepitopes such as H3K27M will be assessed clinically with a particular focus on the identification of specific receptors on neoepitope-specific T cells activated in patients by vaccination. Within a multicenter Phase I study (INTERCEPT H3) funded by the German Cancer Aid and conducted in cooperation with TRON (Mainz), patients with H3K27M-mutated gliomas are treated with an mRNA vaccination against H3K27M combined with the checkpoint inhibitor Atezolizumab. From these patients, H3K27M-specific T cell receptors will be identified using single cell sequencing and then functionally tested. The aim is to use such T cell receptors for treatment with patient-autologous T cell receptor-transgenic T cells by adoptive transfer.

Other collaborative projects deal with the immunomodulating effects of radiotherapy in brain tumors (SFB 1366), resistance mechanisms to checkpoint inhibitors in gliomas (SFB 1389) and brain metastases (GRK 2099), as well as mechanisms of immunomodulation by AHR inhibitors (Future Topic Immunology & Inflammation). Close collaborations exist especially with the Helmholtz Institute for Translational Oncology (HI-TRON), which was founded in 2018.

Combination of comparative TCRB deep sequencing and single cell TCR sequencing for high-throughput TCR discovery. Selected biological samples, e.g., PBMC-derived T cells will be expanded in vitro, e.g., with a neoepitopic 20-mer peptide such as IDH1R132H. E.g., 7000 T cells will be subjected to single cell TCR sequencing to ultimately retrieve 4000 T cells, the rest will be subjected to comparative TCRB deep sequencing. Orange shaded clonotypes, clonotypes of interest, blue shaded clonotypes, expanded by negative control conditions, and violet shaded clonotypes, no differential expansion (Bunse et al., Methods Enzymol 2019).

Iterative therapy development cycle. IDH1R132H - point mutation in the gene for isocitrate dehydrogenase type 1, H3.3K27M - point mutation in the histone-3 gene H3F3A, Trp - l-Tryptophan, AHR - aryl hydrocarbon receptor, TDO - tryptophan-2,3-dioxygenase.

Selected publications

1. Aslan, K., V. Turco, J. Blobner, J. K. Sonner, A. R. Liuzzi, N. G. Nunez, D. De Feo, P. Kickingereder, M. Fischer, E. Green, A. Sadik, M. Friedrich, K. Sanghvi, M. Kilian, F. Cichon, L. Wolf, K. Jahne, A. von Landenberg, L. Bunse, F. Sahm, D. Schrimpf, J. Meyer, A. Alexander, G. Brugnara, R. Roth, K. Pfleiderer, B. Niesler, A. von Deimling, C. Opitz, M. O. Breckwoldt, S. Heiland, M. Bendszus, W. Wick, B. Becher and M. Platten (2020). "Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas." Nat Commun 11(1): 931

2. Sonner JK*, Keil M*, Falk-Paulsen M*, Mishra N, Rehman A, Kramer M, Deumelandt K, Röwe J, Saghvi K, Wolf L, von Landenberg A, Wolff H, Bharti R, Oezen I, Lanz TV, Wanke F, Tang Y, Brandao I, Mohapatra S, Epping L, Grill A, Röth R, Niesler B, Meuth SG, Opitz CA, Okun JG, Reinhardt C, Kurschuss F, Wick W, Bode HB, Rosenstiel P*, Platten M* (2019). Dietary tryptophan links encephalitogenicity of autoreactive T cells with gut microbial ecology. Nat Commun Oct 25 [Epub]. * equal contribution

3. Bunse L, Green EW, Platten M. High-throughput discovery of cancer-targeting TCRs (2019). In: Methods in Enzymology: Tumor Immunology and Immunotherapy. Methods Enzymol 629:419-441.

4. Green EW, Bunse L, Bozza M, Platten M. TCR validation towards gene therapy for cancer (2019). In: Methods in Enzymology: Tumor Immunology and Immunotherapy. Methods Enzymol 629:401-417.

5. Hilf N*, Kuttruff-Coqui S*, Frenzel K, Bukur V, Stevanovic S, Gouttefangeas C, Platten M, Tabatabai G, Dutoit V, von 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 J, Idorn M, Rodon J, Piro J, Poulsen HS, Shraibman B, McCann K, Mendrzyk R, Löwer M, Stieglbauer M, Britten C, Capper D, Welters MJP, Sahuquillo J, Kiesel K, Derhovanessian E, Rusch E, Stockhausen M, Bunse L, Song C, Heesch S, Wagner C, Kemmer-Brueck A, Ludwig J, Schoor O, Tadmor A, Green EW, Fritsche J, Meyer M, Pawlowski N, Dorner S, Maurer D, Weinschenk T, Reinhardt C, Huber C, Rammensee HG, Singh H, Sahin U, Dietrich PY, Wick W (2019). First-in-human trial of actively personalized vaccination in newly diagnosed glioblastoma. Nature 566:240-255. * equal contribution

6. Hilf, N.*, Kuttruff-Coqui, S.*, Frenzel, K., Bukur, V., Stevanovic, S., Gouttefangeas,C., . . . Wick, W. (2019). Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature, 565(7738), 240-245. doi: 10.1038/s41586-018-0810-y* equal contribution

7. Wick W, Dettmer S, Berberich A, Kessler T, Schenkel I, Wick A, Pfaff E, Brors B, Debus J, Unterberg A, Bendszus M, Herold-Mende C, Eisenmenger A, von Deimling A, Jones DTW, Pfister SM, Sahm F, Platten M (2019). Phase I/IIa trials of molecularly matched targeted therapies plus radiotherapy in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation: NCT Neuro Master Match (N²M²) – the NOA-20 trial. Neuro-Oncol 21:95-105.

8. Platten, M., Nollen, E.A.A., Rohrig, U.F., Fallarino, F., & Opitz, C.A. (2019). Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat Rev Drug Discov, 18(5), 379-401. doi: 10.1038/s41573-019-0016-5

9. Bunse, L.*, Pusch, S.*, Bunse, T.*, Sahm, F., Sanghvi, K., Friedrich, M., . . .Deumelandt, K. (2018). Suppression of antitumor t cell immunity by the oncometabolite (r)-2-hydroxyglutarate. Nat. Med, 24, 1192-1203. * equal contribution

10. Ochs, K., Ott, M., Bunse, T., Sahm, F., Bunse, L., Deumelandt, K., . . . Platten, M. (2017). K27m-mutant histone-3 as a novel target for glioma immunotherapy. OncoImmunology, 6(7), e1328340. doi: 0.1080/2162402X.2017.1328340

11. Pusch, S., Krausert, S., Fischer, V., Balss, J., Ott, M., Schrimpf, D., . . . Deimling. A.v. (2017). Pan-mutant idh1 inhibitor bay 1436032 for effective treatment of IDH mutant astrocytoma in vivo. Acta Neuropathologica, 133(4), 629-644. doi: 10.1007/s00401-017-1677-y

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