Neuroimmunology and Brain Tumor Immunology

Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology

Prof. Dr. med. Michael Platten

© 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. Imbalance of such immune control is a hallmark of CNS autoimmunity, while on the other hand, active immunosuppression in the tumor microenvironment of CNS tumors like gliomas hampers effective antitumor immune responses. Our group aims at developing and improving immune therapeutic approaches to target brain tumors by understanding molecular mechanisms of immunosuppression and exploiting novel immunotherapeutic treatment modalities. With expertise in comprehensive cellular and imaging-based analysis of tumor microenvironments, transcriptomics, and immunoreceptor profiling and utilization, and using clinical samples and mouse models, we strongly focus on clinical translation.

In the past years we have identified immunosuppressive functions and mechanisms of key metabolites that are produced by brain tumors. The discovery that TDO-derived tryptophan metabolites (kynurenines) drive growth of brain tumors and immunosuppression via the activation of the aryl hydrocarbon receptor (AHR) opened the way to novel therapeutic targets and implied further questions which we currently address using tumor models. A central goal is the identification of drugs interfering with tryptophan catabolism as potential therapeutics for malignant glioma. Our findings that IDH-mutant glioma cell-derived 2HG actively and directly inhibits adaptive cellular and innate immune responses by affecting immune cell function in the tumor microenvironment pave the way towards novel concepts of immunotherapeutic combination treatments which we are currently investigating in preclinical animal glioma models and chaperoning on their clinical translation.

A second line of investigations addresses the discovery of novel target antigens and T cell receptors for targeted immunotherapy of gliomas. Using an MHC-humanized syngeneic mouse tumor model we have shown therapeutic efficacy of an IDH1 mutation-specific vaccine, providing the first evidence that mutation-specific T helper cell responses are capable to control solid tumors. On that basis we have successfully completed a phase I clinical trial to test immunogenicity and tolerability of this vaccine in brain tumor patients, showing strong immunogenicity, enhanced pseudoprogression as a surrogate marker for immune cell infiltration and successful anti-tumor immune response, and IDH1 mutation-specific T cells infiltrating into this post-vaccine lesion. Ongoing projects now focus on identification of further mutational antigens for specific immunotherapy and on specific TCR discovery for use in transgenic T cell therapy for glioma patients. Here, our main focus lays on long-neglected CD4+ T helper cells. In this regard, a workflow for the development of a patient-specific targeted immunotherapy for patients with gliomas based on mutanome analyses and T cell receptor identification as well as an MHC-humanized mouse glioma model for preclinical testing have been developed. Bioinformatics-based approaches for tumor-infiltrating reactive T cell selection for such TCR discovery based on high throughput state-of-the-art single cell RNA, single cell VDJ, as well as TCRbeta deep sequencing, are boosting these processes and progress.

Contact

Prof. Dr. med. Michael Platten
Neuroimmunology and Brain Tumor Immunology (D170)
Tel: +49 621 3832885
Fax: +49 621 3833807


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

Selected Publications

  • Platten M, Bunse L, Wick A, Bunse T, Cornet LL, Harting I, Sahm F, Sanghvi K, Tan CL, Poschke I, Green E, Justesen S, Behrens GA, Breckwoldt MO, Freitag A, Rother LM, Schmitt A, Schnell O, Hense J, Misch M, Krex D, Stevanovic S, Tabatabai G, Steinbach JP, Bendszus M, von Deimling A, Schmitt M, Wick W. A vaccine targeting mutant IDH1 in newly diagnosed glioma. Nature 2021. DOI: 10.1038/s41586-021-03363-z.
  • Aslan K, Turco V, Blobner J, Sonner JK, Liuzzi AR, Núñez NG, De Feo D, Kickingereder P, Fischer M, Green E, Sadik A, Friedrich M, Sanghvi K, Kilian M, Cichon F, Wolf L, Jähne K, von Landenberg A, Bunse L, Sahm F, Schrimpf D, Meyer J, Alexander A, Brugnara G, Röth R, Pfleiderer K, Niesler B, von Deimling A, Opitz C, Breckwoldt MO, Heiland S, Bendszus M, Wick W, Becher B, Platten M. Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas. Nat Commun. 2020 Feb 18;11(1):931. doi: 10.1038/s41467-020-14642-0.PMID: 32071302 Free PMC article.
  • 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 S0, 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, Eisel J, Poschet G, Weller M, Preusser M, Nadji-Ohl M, Thon N, Burger MC, Harter PN, Ratliff M, Harbottle R, Benner A, Schrimpf D, Okun J, Herold-Mende C, Turcan S, Kaulfuss S, Hess-Stumpp H, Bieback K, Cahill DP, Plate KH, Hänggi D, Dorsch M, Suvà ML, Niemeyer BA, von Deimling A, Wick W, Platten M. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat Med. 2018 Aug;24(8):1192-1203. doi: 10.1038/s41591-018-0095-6. Epub 2018 Jul 9.
  • 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.
to top
powered by webEdition CMS