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  • 1
    In: Neuro-Oncology, 2018, Vol. 20(suppl6), pp.vi9-vi9
    Description: BACKGROUND. VXM01 consists of the attenuated Salmonella Typhi Ty21a delivering a plasmid encoding vascular endothelial growth factor receptor 2 (VEGFR2) into the Peyer’s patches via the oral route of administration. The vaccine elicits a systemic T-cell response targeting VEGFR2. This trial examined safety and tolerability, clinical and immunogenic responses to VXM01 after at least four vaccinations at 10 6 or 10 7 colony-forming units in patients with progressive glioblastoma who have failed at least radiochemotherapy with temozolomide. METHODS. Patients with progressive operable glioblastoma were subjected to VXM01 in one oral administration each on day 1, 3, 5, and 7, and 4-weekly single doses during the tumor follow-up period after surgery. Follow-up was done by safety laboratories and physical examinations, MRI, T-cell immunomonitoring in the peripheral blood, and brain tumor immunohistochemistry. RESULTS. Fourteen patients have been treated with VXM01, three out of them with additional nivolumab. Surgery has been performed in eight patients. Under VXM01 treatment 129 adverse events, mostly unrelated to VXM01, were observed after a median of 7.5 doses per patient. IFN-γ ELISpot analysis showed a detectable VEGFR2–specific T–cell response in 7 out 12 patients measured. In the observation period up to 2 years, seven patients are alive and survived for more than 12 months. Survival correlated with a higher CD8/Treg ratio in progressive and primary tumor, which further increased after VXM01 treatment. In patients with prolonged survival a decrease in intratumoral PD-L1 was measured. In one patient, a strong partial response was observed under VXM01 monotherapy, and a complete response after addition of nivolumab. CONCLUSION: VXM01 was safe, produces detectable specific peripheral immune responses and increased T-cell infiltration in post-vaccine tumor tissue, with a favorable course of disease in five patients. A combination study of VXM01 and anti-PD-L1 avelumab in 30 patients with relapsed glioblastoma has been launched.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    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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  • 3
    Language: English
    In: Journal of immunology (Baltimore, Md. : 1950), 01 October 2017, Vol.199(7), pp.2503-2514
    Description: Heterodimeric IL-27 (p28/EBV-induced gene 3) is an important member of the IL-6/IL-12 cytokine family. IL-27 is predominantly synthesized by mononuclear phagocytes and exerts immunoregulatory functional activities on lymphocytic and nonlymphocytic cells during infection, autoimmunity or neoplasms. There is a great body of evidence on the bidirectional interplay between the autonomic nervous system and immune responses during inflammatory disorders, but so far IL-27 has not been defined as a part of these multifaceted neuroendocrine networks. In this study, we describe the role of catecholamines (as mediators of the sympathetic nervous system) related to IL-27 production in primary mouse macrophages. Noradrenaline and adrenaline dose-dependently suppressed the release of IL-27p28 in LPS/TLR4-activated macrophages, which was independent of α adrenoceptors. Instead, β adrenoceptor activation was responsible for mediating gene silencing of IL-27p28 and EBV-induced gene 3. The β adrenoceptor agonists formoterol and salbutamol mediated suppression of IL-27p28 production, when triggered by zymosan/TLR2, LPS/TLR4, or R848/TLR7/8 activation, but selectively spared the polyinosinic-polycytidylic acid/TLR3 pathway. Mechanistically, β adrenergic signaling reinforced an autocrine feedback loop of macrophage-derived IL-10 and this synergized with inhibition of the JNK pathway for limiting IL-27p28. The JNK inhibitors SP600125 and AEG3482 strongly decreased intracellular IL-27p28 in F4/80CD11b macrophages. In endotoxic shock of C57BL/6J mice, pharmacologic activation of β adrenoceptors improved the severity of shock, including hypothermia and decreased circulating IL-27p28. Conversely, IL-27p28 was 2.7-fold increased by removal of the catecholamine-producing adrenal glands prior to endotoxic shock. These data suggest a novel role of the sympathetic neuroendocrine system for the modulation of IL-27-dependent acute inflammation.
    Keywords: Epinephrine -- Pharmacology ; Interleukins -- Immunology ; Macrophages -- Drug Effects ; Norepinephrine -- Pharmacology
    ISSN: 00221767
    E-ISSN: 1550-6606
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 4
    Language: English
    In: Thrombosis and haemostasis, 31 August 2017, Vol.117(9), pp.1782-1797
    Description: Platelet degranulation at the site of vascular injury prevents bleeding and may affect the chronic vascular wound healing response. Transforming Growth Factor (TGF)-β1 is a major component of platelet α-granules known to accumulating in thrombi. It was our aim to determine the role of TGFβ1 released from activated platelets for neointima formation following arterial injury and thrombosis. Mice with platelet-specific deletion of TGFβ1 (Plt.TGFβ-KO) underwent carotid artery injury. Immunoassays confirmed the absence of active TGFβ1 in platelet releasates and plasma of Plt.TGFβ-KO mice. Whole blood analyses revealed similar haematological parameters, and tail cut assays excluded major bleeding defects. Platelet aggregation and the acute thrombotic response to injury in vivo did not differ between Plt.TGFβ-KO and Plt.TGFβ-WT mice. Morphometric analysis revealed that absence of TGFβ1 in platelets resulted in a significant reduction of neointima formation with lower neointima area, intima-to-media ratio, and lumen stenosis. On the other hand, the media area was enlarged in mice lacking TGFβ1 in platelets and contained increased amounts of proteases involved in latent TGFβ activation, including MMP2, MMP9 and thrombin. Significantly increased numbers of proliferating cells and cells expressing the mesenchymal markers platelet-derived growth factor receptor-β or fibroblast-specific protein-1, and the macrophage antigen F4/80, were observed in the media of Plt.TGFβ-KO mice, whereas the medial smooth muscle-actin-immunopositive area and collagen content did not differ between genotypes. Our findings support an essential role for platelet-derived TGFβ1 for the vascular remodelling response to arterial injury, apparently independent from the role of platelets in thrombosis or haemostasis.
    Keywords: Neointima ; Platelets ; Thrombosis ; Transforming Growth Factor Beta 1 ; Vascular Injury ; Blood Coagulation ; Neointima ; Vascular Remodeling ; Blood Platelets -- Metabolism ; Carotid Artery Injuries -- Blood ; Carotid Artery, Common -- Metabolism ; Thrombosis -- Blood ; Transforming Growth Factor Beta1 -- Blood
    ISSN: 03406245
    E-ISSN: 2567-689X
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  • 8
    In: Neuro-Oncology, 2018, Vol. 20(suppl6), pp.vi8-vi9
    Description: In preclinical studies we have defined IDH1R132H as a clonal neoantigen presented on MHC class II. A peptide vaccine encompassing IDH1R132H induces tumor-specific T helper cell responses effective in controlling syngeneic IDH1R132H-mutant tumors in humanized mouse models. NOA-16 (NCT02454634) is a first-in-man, multicenter, phase I trial testing the safety and immunogenicity of an IDH1R132H peptide in incomplete Freunds adjuvant in patients with newly diagnosed, IDH1R132H mutant WHO °III and °IV astrocytomas. Between September 2015 and October 2016, 32 patients were enrolled in seven German sites. 23 patients (71.9%) received radiochemotherapy with temozolomide, six patients (18.8%) received radiotherapy alone and three patients (9.4%) received temozolomide alone. 249 vaccines were administered, 29 (90.6%) of the patients of the safety set (N=32) and 27 (90.0%) patients of the immunogenicity set (N=30) received all eight vaccines. No regime-limiting toxicity was observed. The majority of the patients (N=29, 90.6%) experienced treatment related adverse events (trAE), 1 (3.1%) of them had treatment related SAE. None of the reported AEs were severe. 28/30 (93.3%) patients, who were evaluable for immunogenicity, displayed mutation-specific T cellular (24/30 (80%)) or humoral (26/30 patients (87%)) immune responses not detectable before vaccination. Until end of study no deaths were observed. 4/32 (12.5 %) patients had PD according to RANO criteria, all other patients (N=28, 87.5%) had SD. 12/32 (37.5%) patients displayed pseudoprogressions after the initiation of the vaccine. Single-cell T cell receptor (TCR) sequencing allowed for the identification of IDH1R132H-specific TCRs. In conclusion, NOA-16 met its primary endpoints by demonstrating safety and immunogenicity of a mutation-specific IDH1R132H peptide vaccine given with standard of care in patients with newly diagnosed IDH1R132H mutant malignant astrocytoma.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 9
    Language: English
    In: Molecular Therapy - Oncolytics, 2016, Vol.3, p.16003
    Description: To target oncolytic measles viruses (MV) to tumors, we exploit the binding specificity of designed ankyrin repeat proteins (DARPins). These DARPin-MVs have high tumor selectivity while maintaining excellent oncolytic potency. Stability, small size, and efficacy of DARPins allowed the generation of MVs simultaneously targeted to tumor marker HER2 and cancer stem cell (CSC) marker EpCAM. For optimization, the linker connecting both DARPins was varied in flexibility and length. Flexibility had no impact on fusion helper activity whereas length had. MVs with bispecific MV-H are genetically stable and revealed the desired double-target specificity. the cytolytic activity of bispecific MVs was superior or comparable to mono-targeted viruses depending on the target cells. therapeutic efficacy of the bispecific viruses was validated in an orthotopic ovarian carcinoma model revealing an effective reduction of tumor mass. Finally, the power of bispecific targeting was demonstrated on cocultures of different tumor cells thereby mimicking tumor heterogeneity , more closely reflecting real tumors. Here, bispecific excelled monospecific viruses in efficacy. DARPin-based targeting domains thus allow the generation of efficacious oncolytic viruses with double specificity, with the potential to handle intratumoral variation of antigen expression and to simultaneously target CSCs and the bulk tumor mass.
    Keywords: Medicine
    ISSN: 2372-7705
    E-ISSN: 2372-7705
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  • 10
    Language: English
    Description: To target oncolytic measles viruses (MV) to tumors, we exploit the binding specificity of designed ankyrin repeat proteins (DARPins). These DARPin-MVs have high tumor selectivity while maintaining excellent oncolytic potency. Stability, small size, and efficacy of DARPins allowed the generation of MVs simultaneously targeted to tumor marker HER2/neu and cancer stem cell (CSC) marker EpCAM. For optimization, the linker connecting both DARPins was varied in flexibility and length. Flexibility had no impact on fusion helper activity whereas length had. MVs with bispecific MV-H are genetically stable and revealed the desired double-target specificity. In vitro, the cytolytic activity of bispecific MVs was superior or comparable to mono-targeted viruses depending on the target cells. In vivo, therapeutic efficacy of the bispecific viruses was validated in an orthotopic ovarian carcinoma model revealing an effective reduction of tumor mass. Finally, the power of bispecific targeting was demonstrated on cocultures of different tumor cells thereby mimicking tumor heterogeneity in vitro, more closely reflecting real tumors. Here, bispecific excelled monospecific viruses in efficacy. DARPin-based targeting domains thus allow the generation of efficacious oncolytic viruses with double specificity, with the potential to handle intratumoral variation of antigen expression and to simultaneously target CSCs and the bulk tumor mass.
    Keywords: Department of Biochemistry ; 570 Life sciences; biology ; 610 Medicine & health
    Source: University of Zurich
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