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Prof. Dr. Michael Platten

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).

Fig. 1: 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.

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.

Fig. 2: Tryptophan catabolism — key organs involved. c) KP metabolites, released by myeloid cells after pro-inflammatory stimulation, suppress T cell responses. d) Trp, Kyn and 3‑hydroxykynurenine (3HK) are transported across the blood–brain barrier and taken up by astrocytes, microglia and neurons. Astrocytes mainly produce the neuroprotective kynurenic acid (KA) whereas microglia produce neurotoxic KP metabolites such as quinolinic acid (QA). 5-HT, 5-hydroxytryptamine (Platten et al., Nat Rev Drug Discov 2019).
Fig. 3: Dietary tryptophan restriction (DTR) alters gut microbiota composition. Relative abundance of significant bacterial indicator genera depicted by a heatmap (Sonner et al., Nat Commun 2019).

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).

Fig. 4: Pathophysiology and immunological consequences of IDH mutations. (Friedrich et al., Curr Opin Oncol 2018)

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.

Fig. 5: Immunohistochemistry of immune cell infiltrations: Confocal microscopy images of Iba1+ (red) macrophages/microglia in the cerebellum of mice. Cross-linked iron oxide nanoparticles (CLIO-FITC, green) were administered 48 hours before imaging. The white and grey masses of brains of the MS animal model show dense infiltrates of macrophages / microglia compared to healthy animals. Most of the infiltrating cells have accumulated CLIO-FITC (Kirschbaum et al., PNAS 2016).
Fig. 6: Enhanced frequencies of PD-L1-expressing macrophages in ICB NR tumors. C57Bl/6 J mice were treated with 250 µg anti-PD-1 and 100 µg antiCTLA-4 (ICB +), or isotype control (C) on d13, d16, and d19 and tumors were monitored by MRI on d13, d19, and d26 post Gl261 injection. a Multiparameter flow cytometry analysis of CNS samples from ICB R, ICB NR, and C on d27. (ICB R n = 5, ICB NR n = 5, C n = 5 animals). tSNE-guided immune cell subset identification using tSNE composite dimensions by multiparameter flow cytometry analysis. Relative frequencies (left) and FlowSOMguided meta-clustering on living and single cells (right) of ICB R, NR, and C CNS tissue (Aslan et al., Nat Commun 2020).

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).

Fig. 7: Representative H&E and IHC stainings in anaplastic WHO grade III glioma tissues (left) and semiquantitative analysis of CD4 and CD8 cells based on IHC stainings of grade II and grade III glioma samples from the NOA-04 collective (right). Circles, all glioma tissues; bars, glioma tissues according to subentity. Numbers represent absolute numbers of tissues. Chi-squared test. O, oligodendroglioma; A, astrocytoma; OA, oligoastrocytoma. (Bunse et al., Nature Medicine 2018)
Fig. 8: Combination of comparative TCRB deep sequencing and single cell TCR sequencing for high-throughput TCR discovery. (A) 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)

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

Selected publications

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.

Contact

Medical Faculty Mannheim
Heidelberg University
Theodor-Kutzer-Ufer 1-3
68167  Mannheim

Phone: +49 621/383-2885
E-Mail: michael.platten@medma.uni-heidelberg.de

 

Photo Credits: #1 FGV-Zentrum, Med. Fakultät Mannheim

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