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Berlin Brandenburg

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  • 1
    Language: English
    In: Nature, 30 April 2015, Vol.520(7549), pp.692-6
    Description: Tumour-specific mutations are ideal targets for cancer immunotherapy as they lack expression in healthy tissues and can potentially be recognized as neo-antigens by the mature T-cell repertoire. Their systematic targeting by vaccine approaches, however, has been hampered by the fact that every patient's tumour possesses a unique set of mutations ('the mutanome') that must first be identified. Recently, we proposed a personalized immunotherapy approach to target the full spectrum of a patient's individual tumour-specific mutations. Here we show in three independent murine tumour models that a considerable fraction of non-synonymous cancer mutations is immunogenic and that, unexpectedly, the majority of the immunogenic mutanome is recognized by CD4(+) T cells. Vaccination with such CD4(+) immunogenic mutations confers strong antitumour activity. Encouraged by these findings, we established a process by which mutations identified by exome sequencing could be selected as vaccine targets solely through bioinformatic prioritization on the basis of their expression levels and major histocompatibility complex (MHC) class II-binding capacity for rapid production as synthetic poly-neo-epitope messenger RNA vaccines. We show that vaccination with such polytope mRNA vaccines induces potent tumour control and complete rejection of established aggressively growing tumours in mice. Moreover, we demonstrate that CD4(+) T cell neo-epitope vaccination reshapes the tumour microenvironment and induces cytotoxic T lymphocyte responses against an independent immunodominant antigen in mice, indicating orchestration of antigen spread. Finally, we demonstrate an abundance of mutations predicted to bind to MHC class II in human cancers as well by employing the same predictive algorithm on corresponding human cancer types. Thus, the tailored immunotherapy approach introduced here may be regarded as a universally applicable blueprint for comprehensive exploitation of the substantial neo-epitope target repertoire of cancers, enabling the effective targeting of every patient's tumour with vaccines produced 'just in time'.
    Keywords: Epitopes, T-Lymphocyte -- Genetics ; Histocompatibility Antigens Class II -- Genetics ; Immunotherapy -- Methods ; Melanoma, Experimental -- Immunology ; Mutation -- Genetics
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 2
    Language: English
    In: Journal of Cleaner Production, 01 December 2015, Vol.108, pp.301-311
    Description: Lithium-ion batteries will play a crucial role in the development of mobile consumer devices, stationary energy storage systems, and electric mobility. The growth in these fields will bring about a surge in the lithium-ion battery market. This leads experts to agree that more effective recycling processes are needed in conjunction with the recycling of lithium. This calls for an entirely revolutionary recycling process which we here have attempted to develop. Our approach uses thermal decomposition of the polyvinylidene fluoride binder to lessen the cohesion of coated active material particles and weaken the adhesion between coating and foil. Then, an air-jet-separator is able to detach the coating powder from the current collector foils while stressing remaining particulate agglomerates. This separation process named ANVIIL (Adhesion Neutralization via Incineration and Impact Liberation) was tested on a laboratory scale with electrode rejects. We compared this to the widely used mechanical recycling process that utilizes a cutting mill to separate the current collector and coating. Intermediates and products were characterized using thermogravimetric analysis, tape adhesion tests, atomic absorption spectroscopy, particle size analysis, and gravimetric sieve analysis. We found that 97.1% w/w of the electrode coating can be regained with aluminum impurities of only 0.1% w/w, 30 times purer than the comparative process. This demonstrates a more effective recycling process than is currently available that also enables the recapture of lithium from the electrode coating.
    Keywords: Lithium-Ion Batteries ; Recycling ; Recovering ; Electrodes ; Scraps ; Active Materials ; Engineering
    ISSN: 0959-6526
    E-ISSN: 1879-1786
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  • 3
  • 4
    In: Nature, 2014
    Description: Monoallelic point mutations of isocitrate dehydrogenase type 1 (IDH1) are an early and defining event in the development of a subgroup of gliomas (1-3) and other types of tumour (4-6). They almost uniformly occur in the critical arginine residue (Arg 132) in the catalytic pocket, resulting in a neomorphic enzymatic function, production of the oncometabolite 2-hydroxyglutarate (2-HG) (7,8), genomic hypermethylation (9-11), genetic instability and malignant transformation (12). More than 70% of diffuse grade II and grade III gliomas carry the most frequent mutation, IDH1(R132H) (ref. 3). From an immunological perspective, IDH1(R132H) represents a potential target for immunotherapy as it is a tumour-specific potential neoantigen with high uniformity and penetrance expressed in all tumour cells (13,14). Here we demonstrate that IDH1(R132H) contains an immunogenic epitope suitable for mutation-specific vaccination. Peptides encompassing the mutated region are presented on major histocompatibility complexes (MHC) class II and induce mutation-specific [CD4.sup.+] T-helper-1 ([T.sub.H]1) responses. [CD4.sup.+] [T.sub.H]1 cells and antibodies spontaneously occurring in patients with IDH1(R132H)-mutated gliomas specifically recognize IDH1(R132H). Peptide vaccination of mice devoid of mouse MHC and transgenic for human MHC class I and II with IDH1(R132H) p123-142 results in an effective MHC class II-restricted mutation-specific antitumour immune response and control of pre-established syngeneic IDH1(R132H)-expressing tumours in a [CD4.sup.+] T-cell-dependent manner. As IDH1(R132H) is presentin all tumour cells of these slow-growing gliomas (15), a mutation-specific anti-IDH1(R132H) vaccine may represent a viable novel therapeutic strategy for IDH1(R132H)-mutated tumours.
    Keywords: Gene Mutation -- Identification And Classification ; Drug Targeting -- Research ; Gliomas -- Care And Treatment ; Gliomas -- Development And Progression ; Oxidoreductases -- Health Aspects ; Immune Response -- Research ; Cancer Research;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 5
  • 6
    Language: English
    In: Journal of Power Sources, 01 January 2015, Vol.273, pp.83-88
    Description: The electrolyte of a used lithium-ion battery from a hybrid electric vehicle (HEV) was investigated. The liquid electrolyte was collected through the pressure valve of these 5 Ah cells. It consists of (29.8 ± 0.2) wt.% dimethyl carbonate (DMC), (21.7 ± 0.1) wt.% ethyl methyl carbonate (EMC), (30.3 ± 0.3) wt.% ethylene carbonate (EC) and (2.2 ± 0.1) wt.% cyclohexyl benzene (CHB) which were identified with GC–MS and quantified with GC–FID. Li (1.29 ± 0.04) mol L and PF were determined with IC as the main ionic species in the solution. Furthermore, BF was clearly identified with IC–ESI–MS, IC–ICP–MS and B NMR and quantified to a concentration of (120.8 ± 8.3) mg L with ICP–OES. The presence of POF (detected with GC–MS), F , PO F , HPO F and H PO (determined with IC–ESI–MS) can be attributed to the reaction of the conducting salt LiPF via PF with traces of water. HPO F and H PO could only be observed in cells which were opened in a laboratory hood under exposure of air humidity. This experiment was done to simulate escaping electrolyte from an HEV battery pack. Furthermore, several alkyl phosphates (identified with GC–MS and IC–ESI–MS) are present in the solution due to further reaction of the different fluorinated phosphates with organic carbonates.
    Keywords: Hybrid Electric Vehicle (Hev) ; Lithium-Ion Battery (Lib) Electrolyte ; Aging ; Electrolyte Decomposition ; Organic Carbonates ; Engineering
    ISSN: 0378-7753
    E-ISSN: 1873-2755
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  • 7
    Language: English
    In: Journal of The Electrochemical Society, 2017, Vol.164(1), pp.A6184-A6191
    Keywords: Engineering ; Chemistry;
    ISSN: 0013-4651
    E-ISSN: 1945-7111
    Source: Electrochemical Society (ECS) (via CrossRef)
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  • 8
    In: Nature, 2016
    Description: Lymphoid organs, in which antigen presenting cells (APCs) are in close proximity to T cells, are the ideal microenvironment for efficient priming and amplification of T-cell responses (1). However, the systemic delivery of vaccine antigens into dendritic cells (DCs) is hampered by various technical challenges. Here we show that DCs can be targeted precisely and effectively in vivo using intravenously administered RNA-lipoplexes (RNA-LPX) based on well-known lipid carriers by optimally adjusting net charge, without the need for functionalization of particles with molecular ligands. The LPX protects RNA from extracellular ribonucleases and mediates its efficient uptake and expression of the encoded antigen by DC populations and macrophages in various lymphoid compartments. RNA-LPX triggers interferon-[alpha] (IFN[alpha]) release by plasmacytoid DCs and macrophages. Consequently, DC maturation in situ and inflammatory immune mechanisms reminiscent of those in the early systemic phase of viral infection are activated (2). We show that RNA-LPX encoding viral or mutant neo-antigens or endogenous selfantigens induce strong effector and memory T-cell responses, and mediate potent IFN[alpha]-dependent rejection of progressive tumours. A phase I dose-escalation trial testing RNA-LPX that encode shared tumour antigens is ongoing. In the first three melanoma patients treated at a low-dose level, IFN[alpha] and strong antigen-specific T-cell responses were induced, supporting the identified mode of action and potency. As any polypeptide-based antigen can be encoded as RNA (3,4), RNA-LPX represent a universally applicable vaccine class for systemic DC targeting and synchronized induction of both highly potent adaptive as well as type-I-IFN-mediated innate immune mechanisms for cancer immunotherapy.
    Keywords: Dendritic Cells -- Health Aspects ; Dendritic Cells -- Genetic Aspects ; Cancer Treatment -- Innovations ; Immunotherapy -- Methods ; Drug Delivery Systems -- Innovations ; Molecular Targeted Therapy -- Innovations;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 9
    Language: English
    In: Cancer Research, 2015, Vol.75
    Keywords: Medical And Health Sciences ; Clinical Medicine ; Cancer And Oncology ; Medicin Och Hälsovetenskap ; Klinisk Medicin ; Cancer Och Onkologi
    ISSN: 0008-5472
    E-ISSN: 15387445
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  • 10
    Language: English
    In: Nature, 13 July 2017, Vol.547(7662), pp.222-226
    Description: T cells directed against mutant neo-epitopes drive cancer immunity. However, spontaneous immune recognition of mutations is inefficient. We recently introduced the concept of individualized mutanome vaccines and implemented an RNA-based poly-neo-epitope approach to mobilize immunity against a spectrum of cancer mutations. Here we report the first-in-human application of this concept in melanoma. We set up a process comprising comprehensive identification of individual mutations, computational prediction of neo-epitopes, and design and manufacturing of a vaccine unique for each patient. All patients developed T cell responses against multiple vaccine neo-epitopes at up to high single-digit percentages. Vaccine-induced T cell infiltration and neo-epitope-specific killing of autologous tumour cells were shown in post-vaccination resected metastases from two patients. The cumulative rate of metastatic events was highly significantly reduced after the start of vaccination, resulting in a sustained progression-free survival. Two of the five patients with metastatic disease experienced vaccine-related objective responses. One of these patients had a late relapse owing to outgrowth of β2-microglobulin-deficient melanoma cells as an acquired resistance mechanism. A third patient developed a complete response to vaccination in combination with PD-1 blockade therapy. Our study demonstrates that individual mutations can be exploited, thereby opening a path to personalized immunotherapy for patients with cancer.
    Keywords: Cancer Vaccines -- Genetics ; Melanoma -- Immunology ; Mutation -- Genetics ; Precision Medicine -- Methods ; RNA -- Genetics
    ISSN: 00280836
    E-ISSN: 1476-4687
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