TY - JOUR A1 - Riedel, Simone S. A1 - Mottok, Anja A1 - Brede, Christian A1 - Bäuerlein, Carina A. A1 - Jordán Garrote, Ana Laura A1 - Ritz, Miriam A1 - Mattenheimer, Katharina A1 - Rosenwald, Andreas A1 - Einsele, Hermann A1 - Bogen, Bjarne A1 - Beilhack, Andreas T1 - Non-Invasive Imaging Provides Spatiotemporal Information on Disease Progression and Response to Therapy in a Murine Model of Multiple Myeloma N2 - Background: Multiple myeloma (MM) is a B-cell malignancy, where malignant plasma cells clonally expand in the bone marrow of older people, causing significant morbidity and mortality. Typical clinical symptoms include increased serum calcium levels, renal insufficiency, anemia, and bone lesions. With standard therapies, MM remains incurable; therefore, the development of new drugs or immune cell-based therapies is desirable. To advance the goal of finding a more effective treatment for MM, we aimed to develop a reliable preclinical MM mouse model applying sensitive and reproducible methods for monitoring of tumor growth and metastasis in response to therapy. Material and Methods: A mouse model was created by intravenously injecting bone marrow-homing mouse myeloma cells (MOPC-315.BM) that expressed luciferase into BALB/c wild type mice. The luciferase in the myeloma cells allowed in vivo tracking before and after melphalan treatment with bioluminescence imaging (BLI). Homing of MOPC-315.BM luciferase+ myeloma cells to specific tissues was examined by flow cytometry. Idiotype-specific myeloma protein serum levels were measured by ELISA. In vivo measurements were validated with histopathology. Results: Strong bone marrow tropism and subsequent dissemination of MOPC-315.BM luciferase+ cells in vivo closely mimicked the human disease. In vivo BLI and later histopathological analysis revealed that 12 days of melphalan treatment slowed tumor progression and reduced MM dissemination compared to untreated controls. MOPC-315.BM luciferase+ cells expressed CXCR4 and high levels of CD44 and a4b1 in vitro which could explain the strong bone marrow tropism. The results showed that MOPC-315.BM cells dynamically regulated homing receptor expression and depended on interactions with surrounding cells. Conclusions: This study described a novel MM mouse model that facilitated convenient, reliable, and sensitive tracking of myeloma cells with whole body BLI in living animals. This model is highly suitable for monitoring the effects of different treatment regimens. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-77978 ER - TY - JOUR A1 - Lauruschkat, Chris D. A1 - Page, Lukas A1 - White, P. Lewis A1 - Etter, Sonja A1 - Davies, Helen E. A1 - Duckers, Jamie A1 - Ebel, Frank A1 - Schnack, Elisabeth A1 - Backx, Matthijs A1 - Dragan, Mariola A1 - Schlegel, Nicolas A1 - Kniemeyer, Olaf A1 - Brakhage, Axel A. A1 - Einsele, Hermann A1 - Loeffler, Juergen A1 - Wurster, Sebastian T1 - Development of a simple and robust whole blood assay with dual co-stimulation to quantify the release of T-cellular signature cytokines in response to Aspergillus fumigatus antigens JF - Journal of Fungi N2 - Deeper understanding of mold-induced cytokine signatures could promote advances in the diagnosis and treatment of invasive mycoses and mold-associated hypersensitivity syndromes. Currently, most T-cellular immunoassays in medical mycology require the isolation of mononuclear cells and have limited robustness and practicability, hampering their broader applicability in clinical practice. Therefore, we developed a simple, cost-efficient whole blood (WB) assay with dual α-CD28 and α-CD49d co-stimulation to quantify cytokine secretion in response to Aspergillus fumigatus antigens. Dual co-stimulation strongly enhanced A. fumigatus-induced release of T-cellular signature cytokines detectable by enzyme-linked immunosorbent assay (ELISA) or a multiplex cytokine assay. Furthermore, T-cell-dependent activation and cytokine response of innate immune cells was captured by the assay. The protocol consistently showed little technical variation and high robustness to pre-analytic delays of up to 8 h. Stimulation with an A. fumigatus lysate elicited at least 7-fold greater median concentrations of key T-helper cell signature cytokines, including IL-17 and the type 2 T-helper cell cytokines IL-4 and IL-5 in WB samples from patients with Aspergillus-associated lung pathologies versus patients with non-mold-related lung diseases, suggesting high discriminatory power of the assay. These results position WB-ELISA with dual co-stimulation as a simple, accurate, and robust immunoassay for translational applications, encouraging further evaluation as a platform to monitor host immunity to opportunistic pathogens. KW - immunoassay KW - biomarker KW - Aspergillus KW - cytokines KW - inflammation KW - adaptive immunity Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241025 SN - 2309-608X VL - 7 IS - 6 ER - TY - JOUR A1 - Maucher, Marius A1 - Srour, Micha A1 - Danhof, Sophia A1 - Einsele, Hermann A1 - Hudecek, Michael A1 - Yakoub-Agha, Ibrahim T1 - Current limitations and perspectives of chimeric antigen receptor-T-cells in acute myeloid leukemia JF - Cancers N2 - Adoptive transfer of gene-engineered chimeric antigen receptor (CAR)-T-cells has emerged as a powerful immunotherapy for combating hematologic cancers. Several target antigens that are prevalently expressed on AML cells have undergone evaluation in preclinical CAR-T-cell testing. Attributes of an ‘ideal’ target antigen for CAR-T-cell therapy in AML include high-level expression on leukemic blasts and leukemic stem cells (LSCs), and absence on healthy tissues, normal hematopoietic stem and progenitor cells (HSPCs). In contrast to other blood cancer types, where CAR-T therapies are being similarly studied, only a rather small number of AML patients has received CAR-T-cell treatment in clinical trials, resulting in limited clinical experience for this therapeutic approach in AML. For curative AML treatment, abrogation of bulk blasts and LSCs is mandatory with the need for hematopoietic recovery after CAR-T administration. Herein, we provide a critical review of the current pipeline of candidate target antigens and corresponding CAR-T-cell products in AML, assess challenges for clinical translation and implementation in routine clinical practice, as well as perspectives for overcoming them. KW - AML KW - CAR-T-cell KW - hematology KW - gene therapy KW - adoptive cell therapy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252180 SN - 2072-6694 VL - 13 IS - 24 ER - TY - JOUR A1 - Lapa, Constantin A1 - Herrmann, Ken A1 - Schirbel, Andreas A1 - Hänscheid, Heribert A1 - Lückerath, Katharina A1 - Schottelius, Margret A1 - Kircher, Malte A1 - Werner, Rudolf A. A1 - Schreder, Martin A1 - Samnick, Samuel A1 - Kropf, Saskia A1 - Knop, Stefan A1 - Buck, Andreas K. A1 - Einsele, Hermann A1 - Wester, Hans-Juergen A1 - Kortüm, K. Martin T1 - CXCR4-directed endoradiotherapy induces high response rates in extramedullary relapsed multiple myeloma JF - Theranostics N2 - C-X-C-motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. We have recently reported promising first-in-man experience with CXCR4-directed endoradiotherapy (ERT) in multiple myeloma (MM). Eight heavily pretreated MM patients underwent a total of 10 ERT cycles (7 patients with 1 cycle and a single patient with 3 cycles). ERT was administered in combination with chemotherapy and autologous stem cell support. End points were occurrence and timing of adverse events, progression-free and overall survival. ERT was overall well tolerated without any unexpected acute adverse events or changes in vital signs. With absorbed tumor doses >30-70 Gy in intra- or extramedullary lesions, significant anti-myeloma activity was observed with 1 patient achieving complete remission and 5/8 partial remission. Directly after ERT major infectious complications were seen in one patient who died from sepsis 22 days after ERT, another patient with high tumor burden experienced lethal tumor lysis syndrome. Median progression-free survival was 54 days (range, 13-175), median overall survival was 223 days (range, 13-313). During follow-up (6 patients available), one patient died from infectious complications, 2/8 from disease progression, the remaining 3/8 patients are still alive. CXCR4-directed ERT was well-tolerated and exerted anti-myeloma activity even at very advanced stage MM with presence of extramedullary disease. Further assessment of this novel treatment option is highly warranted. KW - medicine KW - multiple myeloma KW - PET KW - CXCR4 KW - theranostics Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172095 VL - 7 IS - 6 ER - TY - JOUR A1 - Andersen, Jens Peter A1 - Bøgsted, Martin A1 - Dybkær, Karen A1 - Mellqvist, Ulf-Henrik A1 - Morgan, Gareth J. A1 - Goldschmidt, Hartmut A1 - Dimopoulos, Meletios A. A1 - Einsele, Hermann A1 - San Miguel, Jesús A1 - Palumbo, Antonio A1 - Sonneveld, Pieter A1 - Johnsen, Hans Erik T1 - Global myeloma research clusters, output, and citations: a bibliometric mapping and clustering analysis JF - PLoS ONE N2 - Background International collaborative research is a mechanism for improving the development of disease-specific therapies and for improving health at the population level. However, limited data are available to assess the trends in research output related to orphan diseases. Methods and Findings We used bibliometric mapping and clustering methods to illustrate the level of fragmentation in myeloma research and the development of collaborative efforts. Publication data from Thomson Reuters Web of Science were retrieved for 2005-2009 and followed until 2013. We created a database of multiple myeloma publications, and we analysed impact and co-authorship density to identify scientific collaborations, developments, and international key players over time. The global annual publication volume for studies on multiple myeloma increased from 1,144 in 2005 to 1,628 in 2009, which represents a 43% increase. This increase is high compared to the 24% and 14% increases observed for lymphoma and leukaemia. The major proportion (> 90% of publications) was from the US and EU over the study period. The output and impact in terms of citations, identified several successful groups with a large number of intra-cluster collaborations in the US and EU. The US-based myeloma clusters clearly stand out as the most productive and highly cited, and the European Myeloma Network members exhibited a doubling of collaborative publications from 2005 to 2009, still increasing up to 2013. Conclusion and Perspective Multiple myeloma research output has increased substantially in the past decade. The fragmented European myeloma research activities based on national or regional groups are progressing, but they require a broad range of targeted research investments to improve multiple myeloma health care. KW - multiparametric flow cytometry KW - multiple myeloma KW - consensus statement KW - European experts KW - disorders KW - therapy KW - network Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144214 VL - 10 IS - 1 ER - TY - JOUR A1 - Danhof, Sophia A1 - Rasche, Leo A1 - Mottok, Anja A1 - Steinmüller, Tabea A1 - Zhou, Xiang A1 - Schreder, Martin A1 - Kilian, Teresa A1 - Strifler, Susanne A1 - Rosenwald, Andreas A1 - Hudecek, Michael A1 - Einsele, Hermann A1 - Gerhard-Hartmann, Elena T1 - Elotuzumab for the treatment of extramedullary myeloma: a retrospective analysis of clinical efficacy and SLAMF7 expression patterns JF - Annals of Hematology N2 - Extramedullary disease (EMD) represents a high-risk state of multiple myeloma (MM) associated with poor prognosis. While most anti-myeloma therapeutics demonstrate limited efficacy in this setting, some studies exploring the utility of chimeric antigen receptor (CAR)-modified T cells reported promising results. We have recently designed SLAMF7-directed CAR T cells for the treatment of MM. SLAMF7 is a transmembrane receptor expressed on myeloma cells that plays a role in myeloma cell homing to the bone marrow. Currently, the only approved anti-SLAMF7 therapeutic is the monoclonal antibody elotuzumab, but its efficacy in EMD has not been investigated thoroughly. Thus, we retrospectively analyzed the efficacy of elotuzumab-based combination therapy in a cohort of 15 patients with EMD. Moreover, since the presence of the target antigen is an indispensable prerequisite for effective targeted therapy, we investigated the SLAMF7 expression on extramedullary located tumor cells before and after treatment. We observed limited efficacy of elotuzumab-based combination therapies, with an overall response rate of 40% and a progression-free and overall survival of 3.8 and 12.9 months, respectively. Before treatment initiation, all available EMD tissue specimens (n = 3) demonstrated a strong and consistent SLAMF7 surface expression by immunohistochemistry. Furthermore, to investigate a potential antigen reduction under therapeutic selection pressure, we analyzed samples of de novo EMD (n = 3) outgrown during elotuzumab treatment. Again, immunohistochemistry documented strong and consistent SLAMF7 expression in all samples. In aggregate, our data point towards a retained expression of SLAMF7 in EMD and encourage the development of more potent SLAMF7-directed immunotherapies, such as CAR T cells. KW - plasma cells KW - extramedullary disease KW - monoclonal antibody KW - CD319 KW - CS1 KW - antigen loss Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266468 SN - 1432-0584 VL - 100 IS - 6 ER - TY - JOUR A1 - Philipp-Abbrederis, Kathrin A1 - Herrmann, Ken A1 - Knop, Stefan A1 - Schottelius, Margret A1 - Eiber, Matthias A1 - Lückerath, Katharina A1 - Pietschmann, Elke A1 - Habringer, Stefan A1 - Gerngroß, Carlos A1 - Franke, Katharina A1 - Rudelius, Martina A1 - Schirbel, Andreas A1 - Lapa, Constantin A1 - Schwamborn, Kristina A1 - Steidle, Sabine A1 - Hartmann, Elena A1 - Rosenwald, Andreas A1 - Kropf, Saskia A1 - Beer, Ambros J A1 - Peschel, Christian A1 - Einsele, Hermann A1 - Buck, Andreas K A1 - Schwaiger, Markus A1 - Götze, Katharina A1 - Wester, Hans-Jürgen A1 - Keller, Ulrich T1 - In vivo molecular imaging of chemokine receptor CXCR4 expression in patients with advanced multiple myeloma JF - EMBO Molecular Medicine N2 - CXCR4 is a G-protein-coupled receptor that mediates recruitment of blood cells toward its ligand SDF-1. In cancer, high CXCR4 expression is frequently associated with tumor dissemination andpoor prognosis. We evaluated the novel CXCR4 probe [\(^{68}\)Ga]Pentixafor for invivo mapping of CXCR4 expression density in mice xenografted with human CXCR4-positive MM cell lines and patients with advanced MM by means of positron emission tomography (PET). [\(^{68}\)Ga]Pentixafor PET provided images with excellent specificity and contrast. In 10 of 14 patients with advanced MM [\(^{68}\)Ga]Pentixafor PET/CT scans revealed MM manifestations, whereas only nine of 14 standard [\(^{18}\)F]fluorodeoxyglucose PET/CT scans were rated visually positive. Assessment of blood counts and standard CD34\(^{+}\) flow cytometry did not reveal significant blood count changes associated with tracer application. Based on these highly encouraging data on clinical PET imaging of CXCR4 expression in a cohort of MM patients, we conclude that [\(^{68}\)Ga]Pentixafor PET opens a broad field for clinical investigations on CXCR4 expression and for CXCR4-directed therapeutic approaches in MM and other diseases. KW - FDG PET/CT KW - cells KW - CXCR4/SDF-1 KW - CXCR4 KW - multiple myeloma KW - positron emission tomography KW - chemokine receptor KW - in vivo imaging KW - malignancies KW - involvement KW - microenvironment KW - survival KW - cancer KW - autologous transplantation KW - bone disease Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148738 VL - 7 IS - 4 ER - TY - JOUR A1 - Tsamadou, Chrysanthi A1 - Fürst, Daniel A1 - Vucinic, Vladan A1 - Bunjes, Donald A1 - Neuchel, Christine A1 - Mytilineos, Daphne A1 - Gramatzki, Martin A1 - Arnold, Renate A1 - Wagner, Eva Maria A1 - Einsele, Hermann A1 - Müller, Carlheinz A1 - Schrezenmeier, Hubert A1 - Mytilineos, Joannis T1 - Human leukocyte antigen-E mismatch is associated with better hematopoietic stem cell transplantation outcome in acute leukemia patients JF - Haematologica N2 - The immunomodulatory role of human leukocyte antigen (HLA)-E in hematopoietic stem cell transplantation (HSCT) has not been extensively investigated. To this end, we genotyped 509 10/10 HLA unrelated transplant pairs for HLA-E, in order to study the effect of HLA-E as a natural killer (NK)-alloreactivity mediator on HSCT outcome in an acute leukemia (AL) setting. Overall survival (OS), disease free survival (DFS), relapse incidence (RI) and non-relapse mortality (NRM) were set as endpoints. Analysis of our data revealed a significant correlation between HLA-E mismatch and improved HSCT outcome, as shown by both univariate (53% vs. 38%, P=0.002, 5-year OS) and multivariate (hazard ratio (HR)=0.63, confidence interval (CI) 95%=0.48–0.83, P=0.001) analyses. Further subgroup analysis demonstrated that the positive effect of HLA-E mismatch was significant and pronounced in advanced disease patients (n=120) (5-year OS: 50% vs. 18%, P=0.005; HR=0.40, CI 95%=0.22–0.72, P=0.002; results from univariate and multivariate analyses, respectively). The study herein is the first to report an association between HLA-E incompatibility and improved post–transplant prognosis in AL patients who have undergone matched unrelated HSCT. Combined NK and T cell HLA-E-mediated mechanisms may account for the better outcomes observed. Notwithstanding the necessity for in vitro and confirmational studies, our findings highlight the clinical relevance of HLA-E matching and strongly support prospective HLA-E screening upon donor selection for matched AL unrelated HSCTs. KW - medicine KW - acute leukemia (AL) KW - hematopoietic stem cell transplantation (HSCT) KW - human leukocyte antigen-E (HLA-E) KW - HLA-E matching KW - HSTC outcome Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173325 VL - 102 IS - 11 ER - TY - JOUR A1 - Zhou, Xiang A1 - Dierks, Alexander A1 - Kertels, Olivia A1 - Kircher, Malte A1 - Schirbel, Andreas A1 - Samnick, Samuel A1 - Buck, Andreas K. A1 - Knorz, Sebastian A1 - Böckle, David A1 - Scheller, Lukas A1 - Messerschmidt, Janin A1 - Barakat, Mohammad A1 - Kortüm, K. Martin A1 - Rasche, Leo A1 - Einsele, Hermann A1 - Lapa, Constantin T1 - 18F-FDG, 11C-Methionine, and 68Ga-Pentixafor PET/CT in patients with smoldering multiple myeloma: imaging pattern and clinical features JF - Cancers N2 - This study aimed to explore the correlation between imaging patterns and clinical features in patients with smoldering multiple myeloma (SMM) who simultaneously underwent 18F-FDG, 11C-Methionine, and 68Ga-Pentixafor positron emission tomography/computed tomography (PET/CT). We retrieved and analyzed clinical characteristics and PET imaging data of 10 patients with SMM. We found a significant correlation between bone marrow (BM) plasma cell (PC) infiltration and mean standardized uptake values (SUV\(_{mean}\)) of lumbar vertebrae L2-L4 on 11C-Methionine PET/CT scans (r = 0.676, p = 0.031) and 68Ga-Pentixafor PET/CT scans (r = 0.839, p = 0.002). However, there was no significant correlation between BM involvement and SUV\(_{mean}\) of lumbar vertebrae L2-L4 on 18F-FDG PET/CT scans (r = 0.558, p = 0.093). Similarly, mean target-to-background ratios (TBR\(_{mean}\)) of lumbar vertebrae L2-L4 also correlated with bone marrow plasma cell (BMPC) infiltration in 11C-Methionine PET/CT (r = 0.789, p = 0.007) and 68Ga-Pentixafor PET/CT (r = 0.724, p = 0.018) PET/CT. In contrast, we did not observe a significant correlation between BMPC infiltration rate and TBR\(_{mean}\) in 18F-FDG PET/CT (r = 0.355, p = 0.313). Additionally, on 11C-Methionine PET/CT scans, we found a significant correlation between BMPC infiltration and TBR\(_{max}\) of lumbar vertebrae L2-L4 (r = 0.642, p = 0.045). In conclusion, 11C-Methionine and 68Ga-Pentixafor PET/CT demonstrate higher sensitivity than 18F-FDG PET/CT in detecting BM involvement in SMM. KW - 18F-FDG PET/CT KW - 11C-Methionine PET/CT KW - 68Ga-Pentixafor PET/CT KW - smoldering myeloma Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-211240 SN - 2072-6694 VL - 12 IS - 8 ER - TY - JOUR A1 - White, P. Lewis A1 - Springer, Jan A1 - Wise, Matt P. A1 - Einsele, Hermann A1 - Löffler, Claudia A1 - Seif, Michelle A1 - Prommersberger, Sabrina A1 - Backx, Matthijs A1 - Löffler, Jürgen T1 - A clinical case of COVID-19-associated pulmonary aspergillosis (CAPA), illustrating the challenges in diagnosis (despite overwhelming mycological evidence) JF - Journal of Fungi N2 - The COVID-19 pandemic has resulted in large numbers of patients requiring critical care management. With the established association between severe respiratory virus infection and invasive pulmonary aspergillosis (7.6% for COVID-19-associated pulmonary aspergillosis (CAPA)), the pandemic places a significant number of patients at potential risk from secondary invasive fungal disease. We described a case of CAPA with substantial supporting mycological evidence, highlighting the need to employ strategic diagnostic algorithms and weighted definitions to improve the accuracy in diagnosing CAPA. KW - COVID-19 KW - CAPA KW - diagnostics KW - Aspergillus Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-302438 SN - 2309-608X VL - 8 IS - 1 ER - TY - JOUR A1 - Lüke, Florian A1 - Haller, Florian A1 - Utpatel, Kirsten A1 - Krebs, Markus A1 - Meidenbauer, Norbert A1 - Scheiter, Alexander A1 - Spoerl, Silvia A1 - Heudobler, Daniel A1 - Sparrer, Daniela A1 - Kaiser, Ulrich A1 - Keil, Felix A1 - Schubart, Christoph A1 - Tögel, Lars A1 - Einhell, Sabine A1 - Dietmaier, Wolfgang A1 - Huss, Ralf A1 - Dintner, Sebastian A1 - Sommer, Sebastian A1 - Jordan, Frank A1 - Goebeler, Maria-Elisabeth A1 - Metz, Michaela A1 - Haake, Diana A1 - Scheytt, Mithun A1 - Gerhard-Hartmann, Elena A1 - Maurus, Katja A1 - Brändlein, Stephanie A1 - Rosenwald, Andreas A1 - Hartmann, Arndt A1 - Märkl, Bruno A1 - Einsele, Hermann A1 - Mackensen, Andreas A1 - Herr, Wolfgang A1 - Kunzmann, Volker A1 - Bargou, Ralf A1 - Beckmann, Matthias W. A1 - Pukrop, Tobias A1 - Trepel, Martin A1 - Evert, Matthias A1 - Claus, Rainer A1 - Kerscher, Alexander T1 - Identification of disparities in personalized cancer care — a joint approach of the German WERA consortium JF - Cancers N2 - (1) Background: molecular tumor boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs; (2) Methods: we analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities; (3) Results: the highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed for identifying so-called white spots—regions within our catchment that were relatively underrepresented in WERA MTBs; (4) Conclusions: investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in providing precision oncology and help establishing a joint WERA-wide outreach strategy. KW - precision oncology KW - MTB KW - patient access KW - cancer care KW - outreach KW - real world data KW - outcomes research Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290311 SN - 2072-6694 VL - 14 IS - 20 ER - TY - JOUR A1 - Buck, Andreas K. A1 - Serfling, Sebastian E. A1 - Lindner, Thomas A1 - Hänscheid, Heribert A1 - Schirbel, Andreas A1 - Hahner, Stefanie A1 - Fassnacht, Martin A1 - Einsele, Hermann A1 - Werner, Rudolf A. T1 - CXCR4-targeted theranostics in oncology JF - European Journal of Nuclear Medicine and Molecular Imaging N2 - A growing body of literature reports on the upregulation of C-X-C motif chemokine receptor 4 (CXCR4) in a variety of cancer entities, rendering this receptor as suitable target for molecular imaging and endoradiotherapy in a theranostic setting. For instance, the CXCR4-targeting positron emission tomography (PET) agent [\(^{68}\)Ga]PentixaFor has been proven useful for a comprehensive assessment of the current status quo of solid tumors, including adrenocortical carcinoma or small-cell lung cancer. In addition, [\(^{68}\)Ga]PentixaFor has also provided an excellent readout for hematological malignancies, such as multiple myeloma, marginal zone lymphoma, or mantle cell lymphoma. PET-based quantification of the CXCR4 capacities in vivo allows for selecting candidates that would be suitable for treatment using the theranostic equivalent [\(^{177}\)Lu]/[\(^{90}\)Y]PentixaTher. This CXCR4-directed theranostic concept has been used as a conditioning regimen prior to hematopoietic stem cell transplantation and to achieve sufficient anti-lymphoma/-tumor activity in particular for malignant tissues that are highly sensitive to radiation, such as the hematological system. Increasing the safety margin, pretherapeutic dosimetry is routinely performed to determine the optimal activity to enhance therapeutic efficacy and to reduce off-target adverse events. The present review will provide an overview of current applications for CXCR4-directed molecular imaging and will introduce the CXCR4-targeted theranostic concept for advanced hematological malignancies. KW - CXCR4 KW - theranostics KW - C-X-C motif chemokine receptor 4 KW - [68Ga]PentixaFor KW - [177Lu]PentixaTher KW - [90Y]PentixaTher KW - endoradiotherapy KW - adrenocortical carcinoma KW - multiple myeloma Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324545 VL - 49 IS - 12 ER - TY - JOUR A1 - Berges, Carsten A1 - Kerkau, Thomas A1 - Werner, Sandra A1 - Wolf, Nelli A1 - Winter, Nadine A1 - Hünig, Thomas A1 - Einsele, Hermann A1 - Topp, Max S. A1 - Beyersdorf, Niklas T1 - Hsp90 inhibition ameliorates CD4\(^{+}\) T cell-mediated acute Graft versus Host disease in mice JF - Immunity, Inflammation and Disease N2 - Introduction: For many patients with leukemia only allogeneic bone marrow transplantion provides a chance of cure. Co‐transplanted mature donor T cells mediate the desired Graft versus Tumor (GvT) effect required to destroy residual leukemic cells. The donor T cells very often, however, also attack healthy tissue of the patient inducing acute Graft versus Host Disease (aGvHD)—a potentially life‐threatening complication. Methods: Therefore, we used the well established C57BL/6 into BALB/c mouse aGvHD model to evaluate whether pharmacological inhibition of heat shock protein 90 (Hsp90) would protect the mice from aGvHD. Results: Treatment of the BALB/c recipient mice from day 0 to +2 after allogeneic CD4\(^{+}\) T cell transplantation with the Hsp90 inhibitor 17‐(dimethylaminoethylamino)‐17‐demethoxygeldanamycin (DMAG) partially protected the mice from aGvHD. DMAG treatment was, however, insufficient to prolong overall survival of leukemia‐bearing mice after transplantation of allogeneic CD4\(^{+}\) and CD8\(^{+}\) T cells. Ex vivo analyses and in vitro experiments revealed that DMAG primarily inhibits conventional CD4\(^{+}\) T cells with a relative resistance of CD4\(^{+}\) regulatory and CD8\(^{+}\) T cells toward Hsp90 inhibition. Conclusions: Our data, thus, suggest that Hsp90 inhibition might constitute a novel approach to reduce aGvHD in patients without abrogating the desired GvT effect. KW - Hsp90 KW - leukemia KW - acute Graft versus Host Disease KW - Graft versus Tumor Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168318 VL - 4 IS - 4 ER - TY - JOUR A1 - Luber, Verena A1 - Lutz, Mathias A1 - Abele-Horn, Marianne A1 - Einsele, Hermann A1 - Grigoleit, Götz Ulrich A1 - Mielke, Stephan T1 - Excretion of Ascaris lumbricoides following reduced‐intensity allogeneic hematopoietic stem cell transplantation and consecutive treatment with mebendazole JF - Transplant Infectious Disease N2 - Here, we present the unique case of a 51‐year‐old German patient with multiple myeloma excreting Ascaris lumbricoides in his stool five weeks after allogeneic hematopoietic stem cell transplantation. Stool analysis remained negative for the presence of eggs, and there was no eosinophilia in the peripheral blood at any time around stem cell transplantation. The patient was commenced on a three‐day treatment with mebendazole, which was well tolerated. No serious interactions with the concomitant post‐transplant medication or negative effects on the hematopoiesis were observed, and the myeloma still is in complete remission. To our knowledge, this is the first report on excretion of A lumbricoides in the context of allogeneic stem cell transplantation. The case is remarkable with view to the fact that the parasite has supposedly survived all courses of myeloma treatment including autologous and allogeneic conditioning. Parasitosis with A lumbricoides has a worldwide prevalence of about a billion and is extremely rare in northern Europe. Possibly the patient got infected during a trip to Egypt years before multiple myeloma was diagnosed. KW - sirolimus KW - mycophenolic acid KW - multiple myeloma KW - mebendazole KW - hematopoietic stem cell transplantation KW - Ascaris lumbricoides Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219608 SN - 1399-3062 VL - 22 IS - 1 ER - TY - JOUR A1 - Saraceni, Francesco A1 - Labopin, Myriam A1 - Brecht, Arne A1 - Kröger, Nicolaus A1 - Eder, Matthias A1 - Tischer, Johanna A1 - Labussiere-Wallet, Helene A1 - Einsele, Hermann A1 - Beelen, Dietrich A1 - Bunjes, Donald A1 - Niederwieser, Dietger A1 - Bochtler, Tilman A1 - Savani, Bipin N. A1 - Mohty, Mohamad A1 - Nagler, Arnon T1 - Fludarabine-treosulfan compared to thiotepa-busulfan-fludarabine or FLAMSA as conditioning regimen for patients with primary refractory or relapsed acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT) JF - Journal of Hematology & Oncology N2 - Background Limited data is available to guide the choice of the conditioning regimen for patients with acute myeloid leukemia (AML) undergoing transplant with persistent disease. Methods We retrospectively compared outcome of fludarabine-treosulfan (FT), thiotepa-busulfan-fludarabine (TBF), and sequential fludarabine, intermediate dose Ara-C, amsacrine, total body irradiation/busulfan, cyclophosphamide (FLAMSA) conditioning in patients with refractory or relapsed AML. Results Complete remission rates at day 100 were 92%, 80%, and 88% for FT, TBF, and FLAMSA, respectively (p=0.13). Non-relapse mortality, incidence of relapse, acute (a) and chronic (c) graft-versus-host disease (GVHD) rates did not differ between the three groups. Overall survival at 2years was 37% for FT, 24% for TBF, and 34% for FLAMSA (p=0.10). Independent prognostic factors for survival were Karnofsky performance score and patient CMV serology (p=0.01; p=0.02), while survival was not affected by age at transplant. The use of anti-thymocyte globulin (ATG) was associated with reduced risk of grade III-IV aGVHD (p=0.02) and cGVHD (p=0.006), with no influence on relapse. Conclusions In conclusion, FT, TBF, and FLAMSA regimens provided similar outcome in patients undergoing transplant with active AML. Survival was determined by patient characteristics as Karnofsky performance score and CMV serology, however was not affected by age at transplant. ATG appears able to reduce the incidence of acute and chronic GVHD without influencing relapse risk. KW - Acute myeloid leukemia (AML) KW - Active disease KW - Allogeneic transplantation KW - Sibling donor (MSD) KW - Unrelated donor (UD) KW - Conditioning regimen KW - Fludarabine-treosulfan (FT) KW - Thiotepa-busulfan-fludarabine (TBF) KW - Fludarabine KW - intermediate dose Ara-C KW - amsacrine KW - total body irradiation/busulfan KW - cyclophosphamide (FLAMSA) Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227345 VL - 12 IS - 44 ER - TY - JOUR A1 - Da Vià, Matteo Claudio A1 - Solimando, Antonio Giovanni A1 - Garitano-Trojaola, Andoni A1 - Barrio, Santiago A1 - Munawar, Umair A1 - Strifler, Susanne A1 - Haertle, Larissa A1 - Rhodes, Nadine A1 - Vogt, Cornelia A1 - Lapa, Constantin A1 - Beilhack, Andreas A1 - Rasche, Leo A1 - Einsele, Hermann A1 - Kortüm, K. Martin T1 - CIC Mutation as a Molecular Mechanism of Acquired Resistance to Combined BRAF‐MEK Inhibition in Extramedullary Multiple Myeloma with Central Nervous System Involvement JF - The Oncologist N2 - Combined MEK‐BRAF inhibition is a well‐established treatment strategy in BRAF‐mutated cancer, most prominently in malignant melanoma with durable responses being achieved through this targeted therapy. However, a subset of patients face primary unresponsiveness despite presence of the activating mutation at position V600E, and others acquire resistance under treatment. Underlying resistance mechanisms are largely unknown, and diagnostic tests to predict tumor response to BRAF‐MEK inhibitor treatment are unavailable. Multiple myeloma represents the second most common hematologic malignancy, and point mutations in BRAF are detectable in about 10% of patients. Targeted inhibition has been successfully applied, with mixed responses observed in a substantial subset of patients mirroring the widespread spatial heterogeneity in this genomically complex disease. Central nervous system (CNS) involvement is an extremely rare, extramedullary form of multiple myeloma that can be diagnosed in less than 1% of patients. It is considered an ultimate high‐risk feature, associated with unfavorable cytogenetics, and, even with intense treatment applied, survival is short, reaching less than 12 months in most cases. Here we not only describe the first patient with an extramedullary CNS relapse responding to targeted dabrafenib and trametinib treatment, we furthermore provide evidence that a point mutation within the capicua transcriptional repressor (CIC) gene mediated the acquired resistance in this patient. KW - Multiple myeloma KW - Extramedullary disease KW - Capicua transcriptional repressor KW - Drug resistance KW - BRAF mutation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219549 VL - 25 IS - 2 ER - TY - JOUR A1 - Steinhardt, Maximilian Johannes A1 - Zhou, Xiang A1 - Krummenast, Franziska A1 - Meckel, Katharina A1 - Nickel, Katharina A1 - Böckle, David A1 - Messerschmidt, Janin A1 - Knorz, Sebastian A1 - Dierks, Alexander A1 - Heidemeier, Anke A1 - Lapa, Constantin A1 - Einsele, Hermann A1 - Rasche, Leo A1 - Kortüm, Klaus Martin T1 - Sequential CD38 monoclonal antibody retreatment leads to deep remission in a patient with relapsed/refractory multiple myeloma JF - International Journal of Immunopathology and Pharmacology N2 - We report on a currently 76-year-old female patient with relapsed/refractory (RR) multiple myeloma (MM) treated at our institution. This patient had received six lines of therapy including tandem autologous stem cell transplant, proteasome inhibitor, immunomodulatory drugs and CD38 antibody MOR202. At the last relapse, she progressed during treatment with pomalidomide and MOR202. In an individualized therapy concept, we started a multi-agent salvage therapy with pomalidomide, bortezomib, doxorubicin, dexamethasone, and CD38 antibody daratumumab (“Pom-PAD-Dara”), which resulted in a stringent complete remission with minimal residual disease (MRD) negativity after nine cycles. So far, our patient shows a progression free survival of more than 12 months. Our case demonstrates the feasibility of successful CD38 antibody retreatment in a patient with heavily pretreated CD38 antibody resistant MM. KW - CD38 KW - MOR202 KW - daratumumab KW - multiple myeloma KW - refractory KW - relapse Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236235 VL - 34 ER - TY - JOUR A1 - Vargas, Juan Gamboa A1 - Wagner, Jennifer A1 - Shaikh, Haroon A1 - Lang, Isabell A1 - Medler, Juliane A1 - Anany, Mohamed A1 - Steinfatt, Tim A1 - Mosca, Josefina Peña A1 - Haack, Stephanie A1 - Dahlhoff, Julia A1 - Büttner-Herold, Maike A1 - Graf, Carolin A1 - Viera, Estibaliz Arellano A1 - Einsele, Hermann A1 - Wajant, Harald A1 - Beilhack, Andreas T1 - A TNFR2-Specific TNF fusion protein with improved in vivo activity JF - Frontiers in Immunology N2 - Tumor necrosis factor (TNF) receptor-2 (TNFR2) has attracted considerable interest as a target for immunotherapy. Indeed, using oligomeric fusion proteins of single chain-encoded TNFR2-specific TNF mutants (scTNF80), expansion of regulatory T cells and therapeutic activity could be demonstrated in various autoinflammatory diseases, including graft-versus-host disease (GvHD), experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). With the aim to improve the in vivo availability of TNFR2-specific TNF fusion proteins, we used here the neonatal Fc receptor (FcRn)-interacting IgG1 molecule as an oligomerizing building block and generated a new TNFR2 agonist with improved serum retention and superior in vivo activity. Methods Single-chain encoded murine TNF80 trimers (sc(mu)TNF80) were fused to the C-terminus of an in mice irrelevant IgG1 molecule carrying the N297A mutation which avoids/minimizes interaction with Fcγ-receptors (FcγRs). The fusion protein obtained (irrIgG1(N297A)-sc(mu)TNF80), termed NewSTAR2 (New selective TNF-based agonist of TNF receptor 2), was analyzed with respect to activity, productivity, serum retention and in vitro and in vivo activity. STAR2 (TNC-sc(mu)TNF80 or selective TNF-based agonist of TNF receptor 2), a well-established highly active nonameric TNFR2-specific variant, served as benchmark. NewSTAR2 was assessed in various in vitro and in vivo systems. Results STAR2 (TNC-sc(mu)TNF80) and NewSTAR2 (irrIgG1(N297A)-sc(mu)TNF80) revealed comparable in vitro activity. The novel domain architecture of NewSTAR2 significantly improved serum retention compared to STAR2, which correlated with efficient binding to FcRn. A single injection of NewSTAR2 enhanced regulatory T cell (Treg) suppressive activity and increased Treg numbers by > 300% in vivo 5 days after treatment. Treg numbers remained as high as 200% for about 10 days. Furthermore, a single in vivo treatment with NewSTAR2 upregulated the adenosine-regulating ectoenzyme CD39 and other activation markers on Tregs. TNFR2-stimulated Tregs proved to be more suppressive than unstimulated Tregs, reducing conventional T cell (Tcon) proliferation and expression of activation markers in vitro. Finally, singular preemptive NewSTAR2 administration five days before allogeneic hematopoietic cell transplantation (allo-HCT) protected mice from acute GvHD. Conclusions NewSTAR2 represents a next generation ligand-based TNFR2 agonist, which is efficiently produced, exhibits improved pharmacokinetic properties and high serum retention with superior in vivo activity exerting powerful protective effects against acute GvHD. KW - agonist KW - GvHD KW - regulatory T cells KW - serum retention KW - TNF KW - TNFR2 Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-277436 SN - 1664-3224 VL - 13 ER - TY - JOUR A1 - Fischer, Julia A1 - Knop, Stefan A1 - Danhof, Sophia A1 - Einsele, Hermann A1 - Keller, Daniela A1 - Löffler, Claudia T1 - The influence of baseline characteristics, treatment and depression on health-related quality of life in patients with multiple myeloma: a prospective observational study JF - BMC Cancer N2 - Background Multiple myeloma (MM) is the third most common hematologic malignancy with increasing importance due to improving treatment strategies and long-term outcomes in an aging population. This study aims to analyse influencing factors on health-related quality of life (HRQoL), such as treatment strategies, participation in a clinical trial and patient characteristics like anxiety, depression, gender, and age. A better understanding of the individual factors in context with HRQoL could provide a helpful instrument for clinical decisions. Methods In this prospective observational study, the HRQoL of MM patients with different therapies (first-line and relapse) was quantified by standardized questionnaires (EORTC QLQ-C30 and -MY20) in the context of sociodemographic data, individual anxiety and depressiveness (PHQ-4), and a selected number of clinical parameters and symptoms at defined time-points before, during, and after therapy. Results In total, 70 patients were included in the study. The median age of the study cohort was 62 years. 44% were female and 56% were male patients. More than half of the patients were fully active with an ECOG 0. Global health status was significantly higher in patients with first-line treatment and even increased after start of therapy, while the pain level decreased. In contrast, patients with relapsed MM reported a decreasing global health status and increasing pain. Additionally, there was a higher global health status in less anxious/depressive patients. HRQoL decreased significantly after start of chemotherapy in the parameters body image, side effects of treatment, and cognitive functioning. Tandem stem-cell transplantation was not found to be a risk factor for higher impairment of HRQoL. Participation in a clinical study led to an improvement of most aspects of HRQoL. Among others, increased anxiety and depression, female gender, older age, impaired performance status, and recurrent disease can be early indicators for a reduced HRQoL. Conclusion This study showed the importance of regular longitudinal assessments of patient reported outcomes (PROs) in routine clinical care. For the first time, to our knowledge, we were able to demonstrate a potential impact between participation in clinical trials and HRQoL. However, due to frequently restrictive inclusion criteria for clinical trials, these MM patients might not be directly comparable with patients treated within standard therapy concepts. Further studies are needed to clarify the relevance of this preliminary data in order to develop an individualized, patient-centred, therapy concept. KW - multiple myeloma KW - quality of life KW - participation in clinical trials KW - depression KW - observational Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300435 VL - 22 ER - TY - JOUR A1 - Rydzek, Julian A1 - Nerreter, Thomas A1 - Peng, Haiyong A1 - Jutz, Sabrina A1 - Leitner, Judith A1 - Steinberger, Peter A1 - Einsele, Hermann A1 - Rader, Christoph A1 - Hudecek, Michael T1 - Chimeric Antigen Receptor Library Screening Using a Novel NF-kappa B/NFAT Reporter Cell Platform JF - Molecular Therapy N2 - Chimeric antigen receptor (CAR)-T cell immunotherapy is under intense preclinical and clinical investigation, and it involves a rapidly increasing portfolio of novel target antigens and CAR designs. We established a platform that enables rapid and high-throughput CAR-screening campaigns with reporter cells derived from the T cell lymphoma line Jurkat. Reporter cells were equipped with nuclear factor kappa B (NF kappa B) and nuclear factor of activated T cells (NFAT) reporter genes that generate a duplex output of enhanced CFP (ECFP) and EGFP, respectively. As a proof of concept, we modified reporter cells with CD19-specific and ROR1-specific CARs, and we detected high-level reporter signals that allowed distinguishing functional from non-functional CAR constructs. The reporter data were highly reproducible, and the time required for completing each testing campaign was substantially shorter with reporter cells (6 days) compared to primary CAR-T cells (21 days). We challenged the reporter platform to a large-scale screening campaign on a ROR1-CAR library, and we showed that reporter cells retrieved a functional CAR variant that was present with a frequency of only 6 in 1.05 x 10(6). The data illustrate the potential to implement this reporter platform into the preclinical development path of novel CAR-T cell products and to inform and accelerate the selection of lead CAR candidates for clinical translation. KW - NF-κB/NFAT reporter cells KW - chimeric antigen receptor KW - library screening KW - cancer immunotherapy KW - ROR1 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227193 VL - 27 IS - 2 ER -