UNITE  towards clinical implementation

In response to major changes in diagnostic algorithms and the publication of mature results from various large clinical trials, the European Association of Neuro-Oncology (EANO) recognized the need to provide updated guidelines for the diagnosis and management of adult patients with diffuse gliomas. Through these evidence-based guidelines, a task force of EANO provides recommendations for the diagnosis, treatment and follow-up of adult patients with diffuse gliomas. The diagnostic component is based on the 2016 update of the WHO Classification of Tumors of the Central Nervous System and the subsequent recommendations of the Consortium to Inform Molecular and Practical Approaches to CNS Tumour Taxonomy – Not Officially WHO (cIMPACT-NOW). With regard to therapy, we formulated recommendations based on the results from the latest practice-changing clinical trials and also provide guidance for neuropathological and neuroradiological assessment. In these guidelines, we define the role of the major treatment modalities of surgery, radiotherapy and systemic pharmacotherapy, covering current advances and cognizant that unnecessary interventions and expenses should be avoided. This document is intended to be a source of reference for professionals involved in the management of adult patients with diffuse gliomas, for patients and caregivers, and for health-care providers.

 

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Weller M, van den Bent M, Preusser M, Le Rhun E, Tonn JC, Minniti G, Bendszus M*, Balana C, Chinot O, Dirven L, French P, Hegi ME, Jakola AS, Platten M*, Roth P, Rudà R, Short S, Smits M, Taphoorn MJB, von Deimling A*, Westphal M, Soffietti R, Reifenberger G, Wick W*. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2020 Dec 8. doi: 10.1038/s41571-020-00447-z. Online ahead of print.Nat Rev Clin Oncol. 2020.PMID: 33293629

*UNITE Principle Investigators

 

Research findings related to UNITE work package C04

Aryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity. The context specificity of AHR target genes has so far impeded systematic investigation of AHR activity and its upstream enzymes across human cancers. A pan-tissue AHR signature, derived by natural language processing, revealed that across 32 tumor entities, interleukin-4-induced-1 (IL4I1) associates more frequently with AHR activity than IDO1 or TDO2, hitherto recognized as the main Trp-catabolic enzymes. IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid. It associates with reduced survival in glioma patients, promotes cancer cell motility, and suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice. Immune checkpoint blockade (ICB) induces IDO1 and IL4I1. As IDO1 inhibitors do not block IL4I1, IL4I1 may explain the failure of clinical studies combining ICB with IDO1 inhibition. Taken together, IL4I1 blockade opens new avenues for cancer therapy.

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Sadik A, Somarribas Patterson LF, Öztürk S, Mohapatra SR, Panitz V, Secker PF, Pfänder P, Loth S, Salem H, Prentzell MT, Berdel B, Iskar M, Faessler E, Reuter F, Kirst I, Kalter V, Foerster KI, Jäger E, Guevara CR, Sobeh M, Hielscher T, Poschet G, Reinhardt A, Hassel JC, Zapatka M, Hahn U, von Deimling A*, Hopf C*, Schlichting R, Escher BI, Burhenne J, Haefeli WE*, Ishaque N, Böhme A, Schäuble S, Thedieck K, Trump S, Seiffert M, Opitz CA.*. IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression. Cell. 2020 Aug 17:S0092-8674(20)30946-6. *UNITE Principle Investigators

Research findings related to UNITE work package B01

Intrinsic malignant brain tumors, such as glioblastomas are frequently resistant to immune checkpoint blockade (ICB) with few hypermutated glioblastomas showing response. Modeling patient-individual resistance is challenging due to the lack of predictive biomarkers and limited accessibility of tissue for serial biopsies. Here, Michael Platten et al. investigate resistance mechanisms to anti-PD-1 and anti-CTLA-4 therapy in syngeneic hypermutated experimental gliomas and show a clear dichotomy and acquired immune heterogeneity in ICB-responder and non-responder tumors. They made use of this dichotomy to establish a radiomic signature predicting tumor regression after pseudoprogression induced by ICB therapy based on serial magnetic resonance imaging. They provide evidence that macrophage-driven ICB resistance is established by CD4 T cell suppression and Treg expansion in the tumor microenvironment via the PD-L1/PD-1/CD80 axis. These findings uncover an unexpected heterogeneity of response to ICB in strictly syngeneic tumors and provide a rationale for targeting PD-L1-expressing tumor-associated macrophages to overcome resistance to ICB.

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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. *UNITE Principle Investigators

Research findings related to clinical trial development within UNITE

O6-methylguanine DNA-methyl transferase (MGMT) promoter methylation status is predictive for alkylating chemotherapy, but there are non-benefitting subgroups. The long-term update of NOA-08 compared efficacy and safety of radiotherapy (RT, n=176) and temozolomide at 7/14 days (TMZ, n=193) in patients >65 years with anaplastic astrocytoma or glioblastoma. DNA methylation patterns and copy number variations were assessed in the biomarker cohort of 104 patients and in an independent cohort of 188 patients treated with RT+TMZ-containing regimens in Heidelberg.  Wick et al. showed that MGMT promoter methylation is a strong predictive biomarker for the choice between RT and TMZ. It indicates favorable long-term outcome with initial TMZ monotherapy in patients with MGMT promoter-methylated tumors primarily in the RTK II subgroup.

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Wick A, Kessler T*, Platten M*, Meisner C, Bamberg M, Herrlinger U, Felsberg J, Weyerbrock A, Papsdorf K, Steinbach JP, Sabel M, Vesper J, Debus J, Meixensberger J, Ketter R, Hertler C, Mayer-Steinacker R, Weisang S, Bölting H, Reuss D, Reifenberger G, Sahm F*, von Deimling A*, Weller M, Wick W*; NOA-08 Study Group of the Neurooncology Working Group (NOA) of the German Cancer Society. Superiority of temozolomide over radiotherapy for elderly patients with RTK II methylation class, MGMT promoter-methylated malignant astrocytoma. Neuro Oncol. 2020 Feb 17. pii: noaa033. *UNITE Principle Investigators

 

Research findings related to UNITE work package A01

A network of communicating tumour cells that is connected by tumour microtubes mediates the progression of incurable gliomas. Moreover, neuronal activity can foster malignant behaviour of glioma cells by non-synaptic paracrine and autocrine mechanisms. Here Kuner et al. report a direct communication channel between neurons and glioma cells in different disease models and human tumours: functional bona fide chemical synapses between presynaptic neurons and postsynaptic glioma cells. These neurogliomal synapses show a typical synaptic ultrastructure, are located on tumour microtubes, and produce postsynaptic currents that are mediated by glutamate receptors of the AMPA subtype. Neuronal activity including epileptic conditions generates synchronised calcium transients in tumour-microtube-connected glioma networks. Glioma-cell-specific genetic perturbation of AMPA receptors reduces calcium-related invasiveness of tumour-microtube-positive tumour cells and glioma growth. Invasion and growth are also reduced by anaesthesia and the AMPA receptor antagonist perampanel, respectively. These findings reveal a biologically relevant direct synaptic communication between neurons and glioma cells with potential clinical implications.

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Venkataramani V, Tanev DI, Strahle C, Studier-Fischer A, Fankhauser L, Kessler T*, Körber C, Kardorff M, Ratliff M*, Xie R, Horstmann H, Messer M, Paik SP, Knabbe J, Sahm F, Kurz FT, Acikgöz AA, Herrmannsdörfer F, Agarwal A, Bergles DE, Chalmers A, Miletic H, Turcan S*, Mawrin C, Hänggi D, Liu HK*, Wick W*, Winkler F*, Kuner T. Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature. 2019 Sep;573(7775):532-538. *UNITE Principle Investigators