Neuroimmunology and Brain Tumor Immunology

Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology

Prof. Dr. med. Michael Platten

Immunologic presentation (PLA, red) of a specific mutation (IDH1R132H), green) in two tissue sections of gliomas which are positive for this mutation. In some tissues, tumor cells themselves (blue and green) present the mutation (left), in others, the mutation is presented by stroma cells (only blue) (right).
© dkfz.de

The central nervous system (CNS) is considered an immune privileged organ, where immune responses are tightly controlled through an intensive cross-talk with the peripheral immune system despite the blood-brain barrier. Despite this tight control autoimmunity takes place in the CNS. A paradigmatic autoimmune disease of the CNS is multiple sclerosis (MS). On the other hand, a hallmark of intrinsic CNS tumors like gliomas is an active immunosuppression. The cellular and molecular mechanisms that are involved in the deregulation of CNS immunity are incompletely understood but important to both, too much immune response in MS and too little immune response in brain tumors. Our group is thus interested in the control of CNS autoimmunity and immune therapeutic approaches to brain tumors.

In the past years we have identified key steps in the metabolism of the essential amino acid tryptophan as an endogenous mechanism of inhibition of unwanted immune responses in the context of brain tumors as well as a key receptor of immunosuppressive tryptophan catabolites. These discoveries have led to new insights into the role of tryptophan metabolism in cancer as well as novel targets for therapeutic approaches. The discovery that TDO-derived tryptophan metabolites (kynurenines) drive the growth of brain and probably other types of cancer via the activation of the aryl hydrocarbon receptor (AHR) implied further questions which we currently address using novel animal models in MS and in tumor models. A central goal is the identification of drugs interfering with tryptophan catabolism as potential therapeutics for MS and malignant glioma.

A second line of investigations addresses the discovery of novel target antigens for the immunotherapy of gliomas. To test immunogenicity of a specific mutation, we have developed an MHC-humanized syngeneic mouse tumor model as well as established a novel method to detect the immunological presentation of the mutated antigen in tumor tissue of brain tumor patients. With these tools, we identified specific spontaneous immune responses in brain tumor patients as well as the therapeutic efficacy of a specific vaccine in the mouse model. On the basis of these findings, a phase I clinical study to test immunogenicity and tolerability of this vaccine in brain tumor patients has started recruiting in July 2015. Ongoing projects deal with (a) the mode of action of the vaccine, (b) the identification of neoepitopes in brain tumors for specific immunotherapy, and (c) the conceptual combination with other immunotherapeutic interventions such as immune checkpoint blockers in brain tumors. A workflow for the development of a patient-specific vaccine for patients with gliomas based on mutanome analyses and T cell receptor identification is currently being developed.

Contact

Prof. Dr. med. Michael Platten
Neuroimmunology and Brain Tumor Immunology (G160)
Tel: +49 621 3832885
Fax: +49 621 3833807


Ärztlicher Direktor
Neurologische Klinik
Universitätsmedizin Mannheim
Universität Heidelberg
Theodor-Kutzer-Ufer 1-3
68167 Mannheim

Selected Publications

  • Bunse L, Schumacher T, Sahm F, Pusch S, Oezen I, Rauschenbach K, Gonzalez M, Solecki G, Osswald M, Capper D, Wiestler B, Winkler F, Herold-Mende C, von Deimling A, Wick W, Platten M. Proximity ligation assay evaluates IDH1R132H presentation in gliomas. J Clin Invest. 2015 Feb;125(2):593-606. doi: 10.1172/JCI77780.
  • 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 AG, Vogler I, Diekmann J, Trautwein N, Eichmüller SB, Okun J, Stevanovic 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 Aug 21;512(7514):324-7. doi: 10.1038/nature13387.
  • Lanz TV, Becker S, Osswald M, Bittner S, Schuhmann MK, Opitz CA, Gaikwad S, Wiestler B, Litzenburger UM, Sahm F, Ott M, Iwantscheff S, Grabitz C, Mittelbronn M, von Deimling A, Winkler F, Meuth SG, Wick W, Platten M. Protein kinase Cß as a therapeutic target stabilizing blood-brain barrier disruption in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2013 Sep 3;110(36):14735-40.
  • 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. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature. 2011 Oct 5;478(7368):197-203. doi: 10.1038/nature10491.
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