TY - JOUR A1 - Dietl, Sebastian A1 - Schwinn, Stefanie A1 - Dietl, Susanne A1 - Riedl, Simone A1 - Deinlein, Frank A1 - Rutkowski, Stefan A1 - von Bueren, Andre O. A1 - Krauss, Jürgen A1 - Schweitzer, Tilmann A1 - Vince, Giles H. A1 - Picard, Daniel A1 - Eyrich, Matthias A1 - Rosenwald, Andreas A1 - Ramaswamy, Vijay A1 - Taylor, Michael D. A1 - Remke, Marc A1 - Monoranu, Camelia M. A1 - Beilhack, Andreas A1 - Schlegel, Paul G. A1 - Wölfl, Matthias T1 - MB3W1 is an orthotopic xenograft model for anaplastic medulloblastoma displaying cancer stem cell- and Group 3-properties JF - BMC Cancer N2 - Background Medulloblastoma is the most common malignant brain tumor in children and can be divided in different molecular subgroups. Patients whose tumor is classified as a Group 3 tumor have a dismal prognosis. However only very few tumor models are available for this subgroup. Methods We established a robust orthotopic xenograft model with a cell line derived from the malignant pleural effusions of a child suffering from a Group 3 medulloblastoma. Results Besides classical characteristics of this tumor subgroup, the cells display cancer stem cell characteristics including neurosphere formation, multilineage differentiation, CD133/CD15 expression, high ALDH-activity and high tumorigenicity in immunocompromised mice with xenografts exactly recapitulating the original tumor architecture. Conclusions This model using unmanipulated, human medulloblastoma cells will enable translational research, specifically focused on Group 3 medulloblastoma. KW - cancer stem cells KW - anaplastic medulloblastoma KW - group 3 KW - orthotopic xenograft KW - animal model KW - brain tumor KW - children Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145877 VL - 16 IS - 115 ER - TY - JOUR A1 - Eyrich, Matthias A1 - Rachor, Johannes A1 - Schreiber, Susanne C. A1 - Wölfl, Matthias A1 - Schlegel, Paul G. T1 - Dendritic cell vaccination in pediatric gliomas: lessons learnt and future perspectives JF - Frontiers in Pediatrics N2 - Immunotherapy of malignant gliomas with autologous dendritic cells (DCs) in addition to surgery and radiochemotherapy has been a focus of intense research during the past decade. Since both children and adults are affected by this highly aggressive brain tumor, 10–15% of the several hundred vaccinated patients represent children, making pediatric glioma patients the largest uniform pediatric vaccination cohort so far. In general, DC vaccination in malignant gliomas has been shown to be safe and several studies with a non-vaccinated control group could clearly demonstrate a survival benefit for the vaccinated patients. Interestingly, children and adolescents below 21 years of age seem to benefit even more than adult patients. This review summarizes the findings of the 25 clinical trials published so far and gives a perspective how DC vaccination could be implemented as part of multimodal therapeutic strategies in the near future. KW - pediatrics KW - malignant glioma KW - DC vaccination KW - clinical trial KW - immunotherapy Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-96937 ER - TY - JOUR A1 - Krakow, Sören A1 - Crescimone, Marie L. A1 - Bartels, Charlotte A1 - Wiegering, Verena A1 - Eyrich, Matthias A1 - Schlegel, Paul G. A1 - Wölfl, Matthias T1 - Re-expression of CD14 in response to a combined IL-10/TLR stimulus defines monocyte-derived cells with an immunoregulatory phenotype JF - Frontiers in Immunology N2 - Interleukin 10 is a central regulator of the antigen-presenting function of myeloid cells. It exerts immunomodulatory effects in vivo and induces a regulatory phenotype in monocyte-derived cells in vitro. We analyzed phenotype and function of monocytic cells in vitro in relation to the cytokine milieu and the timing of TLR-based activation. In GM-CSF/IL-4 cultured human monocytic cells, we identified two, mutually exclusive cell populations arising from undifferentiated cells: CD83\(^+\) fully activated dendritic cells and CD14\(^+\) macrophage like cells. Re-expression of CD14 occurs primarily after a sequential trigger with a TLR signal following IL-10 preincubation. This cell population with re-expressed CD14 greatly differs in phenotype and function from the CD83+ cells. Detailed analysis of individual subpopulations reveals that exogenous IL-10 is critical for inducing the shift toward the CD14\(^+\) population, but does not affect individual changes in marker expression or cell function in most cases. Thus, plasticity of CD14 expression, defining a subset of immunoregulatory cells, is highly relevant for the composition of cellular products (such as DC vaccines) as it affects the function of the total product. KW - regulatory dendritic cells KW - MDSC KW - monocyte-derived DC KW - IL-10 KW - macrophages Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201537 VL - 10 IS - 1484 ER - TY - JOUR A1 - Gierlich, Philipp A1 - Lex, Veronika A1 - Technau, Antje A1 - Keupp, Anne A1 - Morper, Lorenz A1 - Glunz, Amelie A1 - Sennholz, Hanno A1 - Rachor, Johannes A1 - Sauer, Sascha A1 - Marcu, Ana A1 - Grigoleit, Götz Ulrich A1 - Wölfl, Matthias A1 - Schlegel, Paul G. A1 - Eyrich, Matthias T1 - Prostaglandin E\(_2\) in a TLR3‑ and 7/8‑agonist‑based DC maturation cocktail generates mature, cytokine‑producing, migratory DCs but impairs antigen cross‑presentation to CD8\(^+\) T cells JF - Cancer Immunology, Immunotherapy N2 - Mature dendritic cells (DCs) represent cellular adjuvants for optimal antigen presentation in cancer vaccines. Recently, a combination of prostaglandin E\(_2\) (PGE\(_2\)) with Toll-like receptor agonists (TLR-P) was proposed as a new standard to generate superior cytokine-producing DCs with high migratory capacity. Here, we compare TLR-P DCs with conventional DCs matured only with the proinflammatory cytokines TNFα and IL-1ß (CDCs), focussing on the interaction of resulting DCs with CD8\(^+\) T-cells. TLR-P matured DCs showed elevated expression of activation markers such as CD80 and CD83 compared to CDCs, together with a significantly higher migration capacity. Secretion of IL-6, IL-8, IL-10, and IL-12 was highest after 16 h in TLR-P DCs, and only TLR-P DCs secreted active IL-12p70. TLR-P DCs as well as CDCs successfully primed multifunctional CD8\(^+\) T-cells from naïve precursors specific for the peptide antigens Melan-A, NLGN4X, and PTP with comparable priming efficacy and T-cell receptor avidity. CD8\(^+\) T-cells primed by TLR-P DCs showed significantly elevated expression of the integrin VLA-4 and a trend for higher T-cell numbers after expansion. In contrast, TLR-P DCs displayed a substantially reduced capability to cross-present CMVpp65 protein antigen to pp65-specific T cells, an effect that was dose-dependent on PGE2 during DC maturation and reproducible with several responder T-cell lines. In conclu-sion, TLR-P matured DCs might be optimal presenters of antigens not requiring processing such as short peptides. However, PGE\(_2\) seems less favorable for maturation of DCs intended to process and cross-present more complex vaccine antigens such as lysates, proteins or long peptides. KW - dendritic cells KW - cancer vaccines KW - prostaglandin E2 KW - TLR agonists KW - tumor-specific CD8+ T cells Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232311 SN - 0340-7004 VL - 69 ER - TY - JOUR A1 - Schilbach, Karin A1 - Alkhaled, Mohammed A1 - Welker, Christian A1 - Eckert, Franziska A1 - Blank, Gregor A1 - Ziegler, Hendrik A1 - Sterk, Marco A1 - Müller, Friederike A1 - Sonntag, Katja A1 - Wieder, Thomas A1 - Braumüller, Heidi A1 - Schmitt, Julia A1 - Eyrich, Matthias A1 - Schleicher, Sabine A1 - Seitz, Christian A1 - Erbacher, Annika A1 - Pichler, Bernd J. A1 - Müller, Hartmut A1 - Tighe, Robert A1 - Lim, Annick A1 - Gillies, Stephen D. A1 - Strittmatter, Wolfgang A1 - Röcken, Martin A1 - Handgretinger, Rupert T1 - Cancer-targeted IL-12 controls human rhabdomyosarcoma by senescence induction and myogenic differentiation JF - OncoImmunology N2 - Stimulating the immune system to attack cancer is a promising approach, even for the control of advanced cancers. Several cytokines that promote interferon-γ-dominated immune responses show antitumor activity, with interleukin 12 (IL-12) being of major importance. Here, we used an antibody-IL-12 fusion protein (NHS-IL12) that binds histones of necrotic cells to treat human sarcoma in humanized mice. Following sarcoma engraftment, NHS-IL12 therapy was combined with either engineered IL-7 (FcIL-7) or IL-2 (IL-2MAB602) for continuous cytokine bioavailability. NHS-IL12 strongly induced innate and adaptive antitumor immunity when combined with IL-7 or IL-2. NHS-IL12 therapy significantly improved survival of sarcoma-bearing mice and caused long-term remissions when combined with IL-2. NHS-IL12 induced pronounced cancer cell senescence, as documented by strong expression of senescence-associated p16\(^{INK4a}\) and nuclear translocation of p-HP1γ, and permanent arrest of cancer cell proliferation. In addition, this cancer immunotherapy initiated the induction of myogenic differentiation, further promoting the hypothesis that efficient antitumor immunity includes mechanisms different from cytotoxicity for efficient cancer control in vivo. KW - TH17 cells KW - cancer-targeted IL-12 KW - differentiation KW - humanized mice KW - immunocytokine KW - immunotherapy KW - M1/M2 macrophages KW - rhabdomyosarcoma KW - TH1-induced senescence KW - tumor-infiltrating lymphocytes Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154579 VL - 4 IS - 7 ER - TY - JOUR A1 - Zlamy, Manuela A1 - Almanzar, Giovanni A1 - Parson, Walther A1 - Schmidt, Christian A1 - Leierer, Johannes A1 - Weinberger, Birgit A1 - Jeller, Verena A1 - Unsinn, Karin A1 - Eyrich, Matthias A1 - Würzner, Reinhard A1 - Prelog, Martina T1 - Efforts of the human immune system to maintain the peripheral CD8+ T cell compartment after childhood thymectomy JF - Immunity & Ageing N2 - Background Homeostatic mechanisms to maintain the T cell compartment diversity indicate an ongoing process of thymic activity and peripheral T cell renewal during human life. These processes are expected to be accelerated after childhood thymectomy and by the influence of cytomegalovirus (CMV) inducing a prematurely aged immune system. The study aimed to investigate proportional changes and replicative history of CD8+ T cells, of recent thymic emigrants (RTEs) and CD103+ T cells (mostly gut-experienced) and the role of Interleukin-(IL)-7 and IL-7 receptor (CD127)-expressing T cells in thymectomized patients compared to young and old healthy controls. Results Decreased proportions of naive and CD31 + CD8+ T cells were demonstrated after thymectomy, with higher proliferative activity of CD127-expressing T cells and significantly shorter relative telomere lengths (RTLs) and lower T cell receptor excision circles (TRECs). Increased circulating CD103+ T cells and a skewed T cell receptor (TCR) repertoire were found after thymectomy similar to elderly persons. Naive T cells were influenced by age at thymectomy and further decreased by CMV. Conclusions After childhood thymectomy, the immune system demonstrated constant efforts of the peripheral CD8+ T cell compartment to maintain homeostasis. Supposedly it tries to fill the void of RTEs by peripheral T cell proliferation, by at least partly IL-7-mediated mechanisms and by proportional increase of circulating CD103+ T cells, reminiscent of immune aging in elderly. Although other findings were less significant compared to healthy elderly, early thymectomy demonstrated immunological alterations of CD8+ T cells which mimic features of premature immunosenescence in humans. KW - thymectomy KW - naive T cells KW - TRECs KW - TCR diversity KW - CMV KW - CD8 KW - telomeres Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146497 VL - 13 IS - 3 ER - TY - JOUR A1 - Zipfel, Julian A1 - Eyrich, Matthias A1 - Schlegel, Paul-Gerhardt A1 - Wiegering, Verena T1 - Disturbed B cell and DC-Homeostasis in Pediatric cGVHD Patients-Cocultivation Experiments and Review of the Literature JF - Clinics in Oncology N2 - B cells and DCs are suspected to play an important role in the pathogenesis of cGvHD, which is a serious complication of HSCT with high morbidity. It is characterized by immune responses of donor immune cells against recipient-derived antigens. athogenesis is not yet fully understood, however reconstitution of B cells after HSCT has similarities to physiologic ontogeny. Immunophenotyping and co-cultivation-experiments of B cells and DCs from pediatric patients with cGvHD as well as healthy donors were conducted. Significant differences between patients and healthy donors were observed with increased memory, transitional, CD69+ and CD86+ phenotype and lower levels of naïve B cells due to apoptosis. Co-cultivation revealed this to be primarily B cell-dependent without major effects of and with DCs. There was a decreased CD11c- phenotype in patients and less apoptosis of DCs. Our data suggest a disturbed homeostasis in B cells with increased memory phenotype in patients, whereas DCs could not influence these differences, therefore DCs are not imposing as promising targets. B cell-dependent approaches should be further investigated. KW - B cell Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-147914 VL - 1 IS - 1097 ER - TY - JOUR A1 - Wiegering, Verena A1 - Schick, Judith A1 - Beer, Meinrad A1 - Gattenlöhner, Stefan A1 - Girschick, Hermann A1 - Liese, Johannes A1 - Schlegel, Paul A1 - Eyrich, Matthias T1 - Varicella-zoster virus infections in immunocompromised patients - a single centre 6-years analysis N2 - Background: Infection with varicella-zoster virus (VZV) contemporaneously with malignant disease or immunosuppression represents a particular challenge and requires individualized decisions and treatment. Although the increasing use of varicella-vaccines in the general population and rapid initiation of VZVimmunoglobulins and acyclovir in case of exposure has been beneficial for some patients, immunocompromised individuals are still at risk for unfavourable courses. Methods: In this single center, 6-year analysis we review incidence, hospitalization and complication rates of VZVinfections in our center and compare them to published data. Furthermore, we report three instructive cases. Results: Hospitalization rate of referred children with VZV-infections was 45%, among these 17% with malignancies and 9% under immunosuppressive therapy. Rate of complications was not elevated in these two high-risk cohorts, but one ALL-patient died due to VZV-related complications. We report one 4-year old boy with initial diagnosis of acute lymphoblastic leukemia who showed a rapidly fatal outcome of his simultaneous varicella-infection, one 1.8-year old boy with an identical situation but a mild course of his disease, and an 8.5-year old boy with a steroiddependent nephrotic syndrome. This boy developed severe hepatic involvement during his varicella-infection but responded to immediate withdrawl of steroids and administration of acyclovir plus single-dose cidofovir after nonresponse to acyclovir after 48 h. Conclusion: Our data show that patients with malignant diseases or immunosuppressive therapy should be hospitalized and treated immediately with antiviral agents. Despite these measures the course of VZV-infections can be highly variable in these patients. We discuss aids to individual decision-making for these difficult situations. KW - Varizellen-Virus KW - varicella-zoster virus immunosuppression KW - pediatrics KW - cidofovir Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68723 ER - TY - JOUR A1 - Wiegering, Verena A1 - Andres, Oliver A1 - Schlegel, Paul G. A1 - Deinlein, Frank A1 - Eyrich, Matthias A1 - Sturm, Alexander T1 - Hyperfibrinolysis and acquired factor XIII deficiency in newly diagnosed pediatric malignancies JF - Haematologica N2 - No abstract available KW - factor XIII deficiency KW - leukemia KW - tumor KW - perioperative bleeding KW - coagulopathy KW - hyperfibrinolysis Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130569 VL - 98 IS - 8 ER - TY - JOUR A1 - Wiegering, Verena A1 - Schmid, Sophie A1 - Andres, Oliver A1 - Wirth, Clemens A1 - Wiegering, Armin A1 - Meyer, Thomas A1 - Winkler, Beate A1 - Schlegel, Paul G. A1 - Eyrich, Matthias T1 - Thrombosis as a complication of central venous access in pediatric patients with malignancies: a 5-year single-center experience N2 - Background Reliable central venous access (CVC) is essential for hematology–oncology patients since frequent puncture of peripheral veins—e.g., for chemotherapy, antibiotic administration, repeated blood sampling, and monitoring—can cause unacceptable pain and psychological trauma, as well as severe side effects in cases of extravasation of chemotherapy drugs. However, CVC lines still carry major risk factors, including thrombosis, infection (e.g., entry site, tunnel, and luminal infections), and catheter dislocation, leakage, or breakage. Methods Here we performed a retrospective database analysis to determine the incidence of CVC-associated thrombosis in a single-center cohort of 448 pediatric oncologic patients, and to analyze whether any subgroup of patients was at increased risk and thus might benefit from prophylactic anticoagulation. Results Of the 448 patients, 269 consecutive patients received a CVC, and 55 of these 269 patients (20%) also had a thrombosis. Of these 55 patients, 43 had at least one CVC-associated thrombosis (total number of CVC-associated thrombosis: n = 52). Among all patients, the median duration of CVC exposure was 464 days. Regarding exposure time, no significant difference was found between patients with and without CVC-associated thrombosis. Subclavia catheters and advanced tumor stages seem to be the main risk factors for the development of CVC-associated thrombosis, whereas pharmacologic prophylaxis did not seem to have a relevant impact on the rate of thrombosis. Conclusions We conclude that pediatric surgeons and oncologists should pay close attention to ensuring optimal and accurate CVC placement, as this appears the most effective tool to minimize CVC-associated complications. KW - Pediatric malignancy KW - Central venous access KW - Port KW - Hickman catheter KW - Thrombosis Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-110476 ER -