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  • 1
    In: Neuro-Oncology, 2018, Vol. 20(1), pp.4-5
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    In: Journal of Neurochemistry, March 2016, Vol.136(6), pp.1142-1154
    Description: We proposed that in malignant gliomas prostaglandin E (PGE) produced by cyclooxygenases (COX) up‐regulates tryptophan‐2,3‐dioxygenase (TDO) expression and enzyme activity through binding to its Gs‐coupled receptor EP4 and therefore may mediate tumor immune escape in part through aryl hydrocarbon receptor (AHR) activation. Moreover, TDO activity itself seems to induce intratumoral PGE metabolism suggesting an immunosuppressive loop involving COX/EP4/TDO.
    Keywords: Tryptophan‐2 ; 3‐Dioxygenase ; Glioma ; Immunosuppression ; Prostaglandin
    ISSN: 0022-3042
    E-ISSN: 1471-4159
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  • 3
    Language: English
    In: PLoS ONE, 2011, Vol.6(5), p.e19823
    Description: 1-methyl-D-tryptophan (1-D-MT) is currently being used in clinical trials in patients with relapsed or refractory solid tumors with the aim of inhibiting indoleamine-2,3-dioxygenase (IDO)-mediated tumor immune escape. IDO is expressed in tumors and tumor-draining lymph nodes and degrades tryptophan (trp) to create an immunsuppressive micromilieu both by depleting trp and by accumulating immunosuppressive metabolites of the kynurenine (kyn) pathway. Here we show that proliferation of alloreactive T-cells cocultured with IDO1-positive human cancer cells paradoxically was inhibited by 1-D-MT. Surprisingly incubation with 1-D-MT increased kyn production of human cancer cells. Cell-free assays revealed that 1-D-MT did not alter IDO1 enzymatic activity. Instead, 1-D-MT induced IDO1 mRNA and protein expression through pathways involving p38 MAPK and JNK signalling. Treatment of cancer patients with 1-D-MT has transcriptional effects that may promote rather than suppress anti-tumor immune escape by increasing IDO1 in the cancer cells. These off-target effects should be carefully analyzed in the ongoing clinical trials with 1-D-MT.
    Keywords: Research Article ; Biology ; Chemistry ; Medicine ; Immunology ; Chemistry ; Molecular Biology ; Oncology ; Pharmacology ; Biochemistry
    E-ISSN: 1932-6203
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  • 4
    Language: German
    In: Der Onkologe, 2017, Vol.23(10), pp.831-837
    Description: To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1007/s00761-017-0258-y Byline: Katharina Ochs (1,2), Lukas Bunse (1,2), Iris Mildenberger (2,3), Wolfgang Wick (1), Michael Platten (1,2,3) Keywords: Glioblastom; Immuncheckpointinhibitor; Neoepitop; EGFRvIII; IDH1R132H-Vakzin; Glioblastoma; Immune checkpoint inhibitor; Neoepitope; EGFRvIII; IDH1R132H vaccine Abstract (German): Hintergrund Immuntherapeutische Behandlungsansatze fur Gliome mit dem Ziel, einerseits gegen den Tumor gerichtete Immunantworten zu starken und andererseits dem immunsuppressiven Tumormikromilieu entgegenzuwirken, werden seit Jahrzehnten in praklinischen und klinischen Studien untersucht, ohne dass es bisher eine zugelassene Immuntherapie fur die Behandlung von primaren Hirntumoren gibt. Dennoch erfahrt die Neuroonkoimmunologie aktuell sowohl aufgrund neuer diagnostischer Moglichkeiten und zielgerichteter Therapieoptionen als auch aufgrund erfolgsversprechender Ergebnisse bei systemischen Tumoren ein gesteigertes Interesse. Ziel Dieser Artikel gibt einen Uberblick uber aktuelle Konzepte zur Immuntherapie bei Gliomen und fasst bisherige Studienergebnisse zusammen. Ergebnisse Wahrend erste klinische Erfahrungen zum Einsatz von Immuncheckpointinhibitoren bei Gliomen keine grundlegenden Sicherheitsbedenken ergaben, scheint auf Grundlage der bisherigen Studienergebnisse die Wirksamkeit zumindest einer Monotherapie in nicht selektierten Patientenpopulationen bei malignen Gliomen begrenzt zu sein. Klinische Ergebnisse zu Kombinationsbehandlungen, beispielsweise mit TaZell-basierten Therapieansatzen wie antigenspezifischen Vakzinierungen, stehen aus. Diese nutzen meist Peptidimpfstoffe, die gegen Tumorantigene gerichtet sind, um eine moglichst effektive und gleichzeitig spezifische Antitumorimmunantwort zu generieren. Neben Impfstoffen gegen individuell variable Antigene eignen sich insbesondere rekurrente Neoepitope wie eine in Glioblastomen vorkommenden Splicevariante des epidermalen Wachstumsfaktors (EGFRvIII) oder eine in diffusen Gliomen vorkommende Punktmutation im Gen der Isocitratdehydrogenase-1 (IDH1R132H) als Vakzinierungsziel. Abstract: Background Immunotherapeutic approaches for treatment of malignant gliomas aim at inducing effective anti-tumor immune responses while counteracting the immunosuppressive tumor microenvironment. Despite extensive preclinical and clinical research during the last decades, there are currently no approved immunotherapeutic drugs for primary brain tumors however, neuro-oncoimmunology is currently experiencing major interest due to new diagnostic and targeted therapy options as well as due to promising results in systemic tumors. Objective This article provides an overview of current concepts for glioma immunotherapy and summarizes the results of available clinical trials. Results While first clinical experiences with the administration of immune checkpoint inhibitors for gliomas did not raise any safety concerns, the efficacy of immune checkpoint monotherapy for malignant gliomas appears to be limited in an unselected patient population. Clinical results on combination treatment, such as T cell-based therapy approaches with antigen-specific vaccinations are pending. This involves mostly peptide vaccines that are directed against tumor antigens in order to generate an effective and at the same time specific anti-tumor immune response. In addition to vaccines against individually variable antigens, recurrent neoepitopes are particularly suitable as a target of vaccination, such as a splice variant of the epidermal growth factor (EGFRvIII) occurring in glioblastomas and a point mutation occurring in diffuse gliomas in the gene of isocitrate dehydrogenase-1 (IDH1R132H). Author Affiliation: (1) Neurologische Universitatsklinik Heidelberg und Nationales Zentrum fur Tumorerkrankungen, Universitatsklinikum Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Deutschland (2) Klinische Kooperationseinheit Neuroimmunologie und Hirntumorimmunologie, Deutsches Krebsforschungszentrum Heidelberg, Heidelberg, Deutschland (3) Neurologische Universitatsklinik Mannheim, Universitatsmedizin Mannheim, Universitat Heidelberg, Theodor-Kutzer-Ufer 1--3, 68167, Mannheim, Deutschland Article History: Registration Date: 23/06/2017 Online Date: 13/07/2017
    Keywords: Glioblastoma ; Immune checkpoint inhibitor ; Neoepitope ; EGFRvIII ; IDH1R132H vaccine
    ISSN: 0947-8965
    E-ISSN: 1433-0415
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  • 5
    Language: English
    In: Prion, 02 September 2016, Vol.10(5), pp.352-361
    Description: Prions and Amyloid beta (Aβ) peptides induce synaptic damage via complex mechanisms that include the pathological alteration of intracellular signaling cascades. The host-encoded cellular prion protein (PrP C ) acts as a high-affinity cell surface receptor...
    Keywords: Alzheimer Disease ; Aβ Peptide ; E-Cadherin ; Endocytosis ; Nmda Receptor ; Neurotransmission ; Prion Protein ; Src Family Kinases ; Synaptic Damage ; Zebrafish ; Biology
    ISSN: 1933-6896
    E-ISSN: 1933-690X
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  • 6
    Language: English
    In: Current Neurology and Neuroscience Reports, 2014, Vol.14(4), pp.1-10
    Description: Gliomas have been viewed for decades as inaccessible for a meaningful antitumor immune response as they grow in a sanctuary site protected from infiltrating immune cells. Moreover, the glioma microenvironment constitutes a hostile environment for an efficient antitumor immune response as glioma-derived factors such as transforming growth factor β and catabolites of the essential amino acid tryptophan paralyze T-cell function. There is growing evidence from preclinical and clinical studies that a meaningful antitumor immunity exists in glioma patients and that it can be activated by vaccination strategies. As a consequence, the concept of glioma immunotherapy appears to be experiencing a renaissance with the first phase 3 randomized immunotherapy trials entering the clinical arena. On the basis of encouraging results from other tumor entities using immunostimulatory approaches by blocking endogenous T-cell suppressive pathways mediated by cytotoxic T-lymphocyte antigen 4 or programmed cell death protein 1/programmed cell death protein 1 ligand 1 with humanized antibodies, there is now a realistic and promising option to combine active immunotherapy with agents blocking the immunosuppressive microenvironment in patients with gliomas to allow a peripheral antitumor immune response induced by vaccination to become effective. Here we review the current clinical and preclinical evidence of antimicroenvironment immunotherapeutic strategies in gliomas.
    Keywords: Tryptophan ; Kynurenine ; Tryptophan 2,3-dioxygenase ; Indoleamine 2,3-dioxygenase ; Aryl hydrocarbon receptor ; Cytotoxic T-lymphocyte antigen 4 ; Programmed cell death protein 1
    ISSN: 1528-4042
    E-ISSN: 1534-6293
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  • 7
    Language: English
    In: Frontiers in cell and developmental biology, 2014, Vol.2, pp.63
    Description: The ability of the cellular prion protein (PrP(C)) to trigger intracellular signals appears central to neurodegeneration pathways, yet the physiological significance of such signals is rather puzzling. For instance, PrP(C) deregulation disrupts phenomena as diverse as synaptic transmission in mammals and cell adhesion in zebrafish. Although unrelated, the key proteins in these events -the NMDA receptor (NMDAR) and E-cadherin, respectively- are similarly modulated by the Src family kinase (SFK) Fyn. These observations highlight the importance of PrP(C)-mediated Fyn activation, a finding reported nearly two decades ago. Given their complex functions and regulation, SFKs may hold the key to intriguing aspects of PrP biology such as its seemingly promiscuous functions and the lack of strong phenotypes in knockout mice. Here we provide a mechanistic perspective on how SFKs might contribute to the uncertain molecular basis of neuronal PrP phenotypes affecting ion channel activity, axon myelination and olfactory function. In particular, we discuss SFK target proteins involved in these processes and the role of tyrosine phosphorylation in the regulation of their activity and cell surface expression.
    Keywords: Src Family Kinases ; Endocytosis ; Ion Channels ; Knockout Mice ; Myelination ; Prion Protein ; Tyrosine Phosphorylation ; Zebrafish
    ISSN: 2296-634X
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  • 8
    In: Current Opinion in Neurology, 2017, Vol.30(6), pp.650-658
    Description: PURPOSE OF REVIEW: Also owing to the limited efficacy of targeted therapies, there has been a renewed interest in targeting gliomas with immunotherapy. But despite considerable efforts using sophisticated approaches, proof of efficacy beyond case studies is still lacking. The purpose of this review is to summarize and discuss current immunotherapeutic approaches and efforts to understand mechanisms of response and resistance. RECENT FINDINGS: The recent failure of large randomized clinical trials using targeted vaccines and checkpoint inhibitors to improve clinical outcome have underlined the grand challenges in this therapeutic arena and illustrated the necessity to understand the biology of immunotherapeutic interventions before conducting large randomized studies. However, these failures should not distract us from continuing to optimize immunotherapeutic concepts. The recent developments in transgenic T cell technologies and personalized vaccines but also rational combinatorial approaches offer tremendous opportunities and should be exploited carefully in early scientifically driven clinical trials. SUMMARY: A profound understanding of the cellular and molecular mechanisms of response and resistance to immunotherapy to be gained from these thoroughly designed clinical trials will be essential to carve out successful strategies in selected patient populations.
    Keywords: Central Nervous System Neoplasms -- Therapy ; Glioma -- Therapy ; Immunotherapy -- Methods;
    ISSN: 1350-7540
    E-ISSN: 14736551
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  • 9
    Language: English
    In: Current Treatment Options in Neurology, 2018, Vol.20(5), pp.1-9
    Description: To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1007/s11940-018-0498-1 Byline: Michael Platten (1,2), Lukas Bunse (1,3), Dennis Riehl (1,4), Theresa Bunse (1,2), Katharina Ochs (1,3), Wolfgang Wick (3,5) Keywords: Glioma; Immunotherapy; Neoepitope; Vaccine; IDH1; Personalized Abstract: Purpose of review To discuss the current state of glioma vaccine development and highlight the challenges associated with clinical implementation of these approaches. Recent findings Vaccination strategies against gliomas have matured considerably during the past years, although proof-of efficacy from controlled clinical trials is still lacking. Advances in antigen discovery, including the definition of neoepitopes including epidermal growth factor receptor variant III (EGFRvIII), isocitrate dehydrogenase (IDH)1R132H and Histone (H)3.3K27M, using multi-omic approaches and computational algorithms allow targeting single antigens, but also implementing truly personalized approaches. In addition, new concepts of vaccine manufacturing including RNA and DNA vaccines improve immunogenicity and applicability in personalized settings. Summary As an increasing amount of clinical data defy the concept of the central nervous system (CNS) as a strictly immunoprivileged site, novel vaccine approaches enter the clinic including critical efforts to identify biomarkers of response and resistance and strategies to overcome the immunosuppressive glioma microenvironment. Author Affiliation: (1) 0000 0004 0492 0584, grid.7497.d, DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center, INF 280, 69120, Heidelberg, Germany (2) 0000 0001 2190 4373, grid.7700.0, Department of Neurology, Mannheim Medical Center, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany (3) 0000 0001 2190 4373, grid.7700.0, Department of Neurology, Heidelberg Medical Center, University of Heidelberg, INF 400, 69120, Heidelberg, Germany (4) 0000 0001 0328 4908, grid.5253.1, Immune Monitoring Unit, DKTK, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany (5) 0000 0004 0492 0584, grid.7497.d, DKTK Clinical Cooperation Unit Neurooncology, German Cancer Research Center, INF 280, 69120, Heidelberg, Germany Article History: Registration Date: 12/03/2018 Online Date: 28/03/2018 Article note: This article is part of the Topical Collection on Neuro-oncology
    Keywords: Glioma ; Immunotherapy ; Neoepitope ; Vaccine ; IDH1 ; Personalized
    ISSN: 1092-8480
    E-ISSN: 1534-3138
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  • 10
    Language: English
    In: Frontiers in immunology, 2014, Vol.5, pp.673
    Description: The tryptophan (TRP) to kynurenine (KYN) metabolic pathway is now firmly established as a key regulator of innate and adaptive immunity. A plethora of preclinical models suggests that this immune tolerance pathway - driven by the key and rate-limiting enzymes indoleamine-2,3-dioxygenase and TRP-2,3-dioxygenase - is active in cancer immunity, autoimmunity, infection, transplant rejection, and allergy. Drugs targeting this pathway, specifically indoleamine-2,3-dioxygenase, are already in clinical trials with the aim at reverting cancer-induced immunosuppression. In the past years, there has been an increase in our understanding of the regulation and downstream mediators of TRP metabolism, such as the aryl hydrocarbon receptor as a receptor for KYN and kynurenic acid. This more detailed understanding will expand our opportunities to interfere with the pathway therapeutically on multiple levels. Here, we discuss the perspective of targeting TRP metabolism at these different levels based on reviewing recent insight into the regulation of TRP metabolism and its downstream effectors.
    Keywords: Ahr ; Ido ; Tdo ; Tryptophan Metabolism ; Tumor Immunity
    ISSN: 1664-3224
    E-ISSN: 20450915
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