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Neurology - Neuroinflammation
The central nervous system (CNS) is regarded as an immune-privileged organ in which immune responses are strictly controlled by intensive exchange with the peripheral immune system despite the blood-brain barrier. Despite this strict control, autoimmune diseases can occur in the CNS. A paradigmatic disease is multiple sclerosis (MS). In contrast, intrinsic brain tumors of the CNS, especially gliomas, often lead to immunosuppression through active processes.
Our Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology – a joint research division of the Medical Faculty Mannheim, Heidelberg University and the German Cancer Research Center aims at understanding and therapeutically exploiting the control of CNS autoimmunity and at developing novel immunotherapeutic approaches for brain tumors. To this end, we are developing innovative animal models and working with patient material. The overall aim of these works is the rapid translation of the findings into clinical studies and to implement an iterative cycle of target discovery and treatment development (Figure 1).
These efforts are embedded in several collaborative research efforts such as the Collaborative Research Centers SFB1389 and SFB1366, the Hertie Network of Excellence in Clinical Neuroscience, the Research Training Group 2099, the Helmholtz Future Topic Immunology and Inflammation, the German Cancer Consortium and the Helmholtz Institute for Translational Oncology.
Metabolic control of autoimmunity and antitumor immunity
In recent years, we have identified key metabolic events that regulate immune responses in the context of multiple sclerosis and brain tumors These findings have opened new perspectives on the development of immunotherapeutic drugs.
The finding that tryptophan metabolites (kynurenines) generated by the activity of tryptophan-2,3-dioxygenase (TDO) promote tumor growth by activating the aryl hydrocarbon receptor (AHR) and suppresses neuroinflammation – also through modulating the gut microbiome - raises a number of further questions that we are trying to answer with the help of new MS animal models and tumor models (Figure 2 and 3). A key goal is to identify drugs that interfere with tryptophan catabolism as a possible treatment for MS, malignant gliomas and other types of cancer. An AHR inhibitor developed within the DKFZ-Bayer Immunooncology Alliance is currently undergoing Phase 1 clinical testing.
Certain types of brain tumors harbor oncogenic mutations in the gene for isocitrate dehydrogenase type 1 (IDH1) resulting in the accumulation of 2-hydroxyglutarate (2-HG), an oncometabolite that drives progression of brain tumors. The discovery that 2-HG is taken up by tumor-infiltrating immune cells and paralyzes their function opens new therapeutic options for 2-HG inhibitors in the context of immunotherapy for brain tumors (Figure 4).
Plasticity and function of myeloid cells in the CNS
Tumor-infiltrating myeloid cells play a key role in the immune response against brain tumors. Although these cells initiate and amplify immune responses against the tumor, cancer cells use tumor-infiltrating myeloid cells to promote tumor growth by angiogenesis and immunosuppression. A high density of these tumor infiltrating myeloid cells is associated with a poor prognosis. Although some of the crucial molecular processes in tumor infiltrating myeloid cells are known, such as the expression of checkpoint inhibitors on macrophages or the activation of certain metabolic processes (TDO/IDO activation), there is still a lack of concrete targets for a targeted therapy against the tumor promoting effect of the myeloid cells (Figure 5 and 6).
Therefore, the aim of our work is to identify new targets for the modulation of immunity in the CNS with regard to autoimmunity and tumor immunity in the CNS as well as in the context of neurodegenerative and psychiatric diseases. New imaging parameters should help to assess the dynamic changes of this immune compartment in animal models and in patients.
Antigen-specific T cell immunity
A particular focus in recent years has been on the identification of mutation-specific T cell responses to brain tumors and its therapeutic exploitation for tumor vaccines. Based on the preclinical characterization of an antigen-specific brain tumor vaccine according to human brain tumor tissue and humanized mouse modes we have demonstrated safety and immunogenicity of this vaccine in a publicly funded multicenter first-in-man phase 1 clinical trial supported by the Neurooncology Working Group of the German Cancer Society. To understand the complex immunological response to treatment a multicenter phase 1 window-of-opportunity trial is currently being conducted. Platforms to identify and functionally test tumor-reactive T cells from brain tumor tissue have recently been established and validated in a clinical trial (Figure 7 and 8).
Selected national and international joint research projects
Hertie Network of Excellence in clinical neuroscience
REsolvInG ImmuNITy to targEt Brain Tumors (RE-IGNITE). Joint project with Maximilian Häussler.
RTG2099 - Hallmarks of Skin Cancer. Subproject “Response and Resistance to Checkpoint Blockade in Melanoma Brain Metastases”.
Mechanisms of response and resistance to checkpoint blockade in gliomas. German Research Foundation – Collaborative Research Program “Understanding and targeting Resistance in Glioblastoma” SFB1389-TPB01. Joint project with Theresa Bunse
Vascular control of neuroinflammation. German Research Foundation – Collaborative Research Program SFB1366-TPC01. Joint project with Katharina Sahm (née Ochs).
Deutsche Forschungsgemeinschaft - Impact of dietary tryptophan on the gut microbiome and autoimmune neuroinflammation (Microbiom).
AMPLIFYing NEOepitope-specific VACcine Responses in progressive diffuse gliomas (AMPLIFY-NEOVAC)
Individualisierte Präzisionsimmuntherapie von Hirntumorpatienten
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.
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
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.
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.
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
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.
Platten M, Fallarino F, Nollen E, Opitz C (2019). Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat Rev Drug Discov 18:379-401.
Bunse L*, Pusch S*, Bunse T*, Sahm F, Sanghvi K, Friedrich M, Alansary D, Sonner JK, Green E, Deumelandt K, Kilian M, Neftel C, Uhlig S, Kessler T, von Landenberg A, Berghoff AS, Marsh K, Steadman M, Zhu D, Nicolay B, Wiestler B, Breckwoldt MO, Al-Ali R, Karcher-Bausch S, Bozza M, Oezen I, Kramer M, Meyer J, Habel A, Poschet G, Weller M, Preusser M, Nadji-Ohl M, Thon N, Burger M, Harter P, Ratliff M, Harbottle R, Benner A, Schrimpf D, Okun J, Herold-Mende CM, Turcan S, Kaulfuss S, Hess-Stumpp H, Bieback K, Cahill DP, Plate KH, Hänggi D, Dorsch M, Suva M, Niemeyer BA, von Deimling A, Wick W, Platten M (2018). Suppression of antitumor T cell immunity by the oncometabolite R-2-hydroxyglutarate. Nat Med 24:1192-1203. * equal contribution
Kirschbaum K*, Sonner J*, Zeller M, Deumelandt K, Bode J, Sharma R, Krüwel T, Fischer M, Hoffmann A, Costa da Silva M, Muckenthaler MU, Wick W, Tews B, Chen JW, Heiland S, Bendszus M, Platten M, Breckwoldt MO (2016). In vivo nanoparticle imaging of the innate immune cell compartment can serve as a biomarker of disease severity in a mouse model of multiple sclerosis. PNAS 113:13227-13232. * equal contribution
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 S, Okun J, Stefanovic S, Riemer AB, Sahin U, Friese M, Beckhove P, von Deimling A, Wick W, Platten M (2014). A vaccine targeting mutant IDH1 induces antitumor immunity. Nature 512:324-327. *equal contribution.
Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M (2011). An endogenous ligand of the human aryl hydrocarbon receptor promotes tumor formation. Nature 478:197-203.
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