28 results on '"Uharek, Lutz"'
Search Results
2. Clinical translation and regulatory aspects of CAR/TCR-based adoptive cell therapies—the German Cancer Consortium approach.
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Krackhardt, Angela M., Anliker, Brigitte, Hildebrandt, Martin, Bachmann, Michael, Eichmüller, Stefan B., Nettelbeck, Dirk M., Renner, Matthias, Uharek, Lutz, Willimsky, Gerald, Schmitt, Michael, Wels, Winfried S., and Schüssler-Lenz, Martina
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T cells ,CELLULAR therapy ,GENE therapy ,THERAPEUTICS ,CANCER treatment - Abstract
Adoptive transfer of T cells genetically modified by TCRs or CARs represents a highly attractive novel therapeutic strategy to treat malignant diseases. Various approaches for the development of such gene therapy medicinal products (GTMPs) have been initiated by scientists in recent years. To date, however, the number of clinical trials commenced in Germany and Europe is still low. Several hurdles may contribute to the delay in clinical translation of these therapeutic innovations including the significant complexity of manufacture and non-clinical testing of these novel medicinal products, the limited knowledge about the intricate regulatory requirements of the academic developers as well as limitations of funds for clinical testing. A suitable good manufacturing practice (GMP) environment is a key prerequisite and platform for the development, validation, and manufacture of such cell-based therapies, but may also represent a bottleneck for clinical translation. The German Cancer Consortium (DKTK) and the Paul-Ehrlich-Institut (PEI) have initiated joint efforts of researchers and regulators to facilitate and advance early phase, academia-driven clinical trials. Starting with a workshop held in 2016, stakeholders from academia and regulatory authorities in Germany have entered into continuing discussions on a diversity of scientific, manufacturing, and regulatory aspects, as well as the benefits and risks of clinical application of CAR/TCR-based cell therapies. This review summarizes the current state of discussions of this cooperative approach providing a basis for further policy-making and suitable modification of processes. [ABSTRACT FROM AUTHOR]
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- 2018
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3. Prospective evaluation of the Septi FAST multiplex real-time PCR assay for surveillance and diagnosis of infections in haematological patients after allogeneic stem cell transplantation compared to routine microbiological assays and an in-house real-time PCR method
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Elges, Sandra, Arnold, Renate, Liesenfeld, Oliver, Kofla, Grzegorz, Mikolajewska, Agata, Schwartz, Stefan, Uharek, Lutz, and Ruhnke, Markus
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DIAGNOSTIC use of polymerase chain reaction ,POLYMERIZATION reactors ,HEMATOLOGIC malignancies ,GENETICS of staphylococcus aureus infections ,GENETICS of bacterial diseases ,GENETICS - Abstract
We prospectively evaluated a multiplex real-time PCR assay (SeptiFast, SF) in a cohort of patients undergoing allo- BMT in comparison to an in-house PCR method ( IH- PCR). Overall 847 blood samples (mean 8 samples/patient) from 104 patients with haematological malignancies were analysed. The majority of patients had acute leukaemia (62%) with a mean age of 52 years (54% female). Pathogens could be detected in 91 of 847 (11%) samples by SF compared to 38 of 205 (18.5%) samples by BC, and 57 of 847 (6.7%) samples by IH- PCR. Coagulase-negative staphylococci (n=41 in SF, n=29 in BC) were the most frequently detected bacteria followed by Escherichia coli (n=9 in SF, n=6 in BC). Candida albicans (n=17 in SF, n=0 in BC, n=24 in IH- PCR) was the most frequently detected fungal pathogen. SF gave positive results in 5% of samples during surveillance vs in 26% of samples during fever episodes. Overall, the majority of blood samples gave negative results in both PCR methods resulting in 93% overall agreement resulting in a negative predictive value of 0.96 (95% CI: 0.95-0.97), and a positive predictive value of 0.10 (95% CI: −0.01 to 0.21). SeptiFast appeared to be superior over BC and the IH- PCR method. [ABSTRACT FROM AUTHOR]
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- 2017
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4. Impact of telomere length on the outcome of allogeneic stem cell transplantation for poor-risk chronic lymphocytic leukaemia: results from the GCLLSG CLL3X trial.
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Scheffold, Annika, Jebaraj, Billy Michael Chelliah, Jaramillo, Sonia, Tausch, Eugen, Steinbrecher, Daniela, Hahn, Michael, Böttcher, Sebastian, Ritgen, Matthias, Bunjes, Donald, Zeis, Matthias, Stadler, Michael, Uharek, Lutz, Scheid, Christoph, Hegenbart, Ute, Hallek, Michael, Kneba, Michael, Schmitz, Norbert, Döhner, Hartmut, Dreger, Peter, and Stilgenbauer, Stephan
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LYMPHOCYTIC leukemia ,STEM cell transplantation ,TELOMERES ,STEM cell treatment ,CHROMOSOMES ,LEUKEMIA treatment ,THERAPEUTICS - Abstract
The article reports on a study which investigated the impact of telomere length on the outcome of allogeneic stem cell transplantation (SCT) for patients with poor risk chronic lymphocytic leukaemia (CLL) based on the German CLL3X trial which included 100 patients. Topics covered include association of telomere length with clinical characteristics, and analysis of telomere length using quantitative polymerase chain reaction.
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- 2017
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5. Association between low uric acid levels and acute graft-versus-host disease.
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Ostendorf, Benjamin, Blau, Olga, Uharek, Lutz, Blau, Igor, and Penack, Olaf
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DISEASE risk factors ,GRAFT versus host disease ,URIC acid ,HEMATOPOIETIC stem cell transplantation ,UNIVARIATE analysis ,ANALYSIS of variance ,MORTALITY ,DISEASE relapse - Abstract
Endogenous danger signals are increasingly recognized in the pathogenesis of graft-versus-host disease (GVHD). Uric acid (UA) is a known danger signal and is released from injured cells during conditioning for allogeneic hematopoietic stem cell transplantation (HSCT), but its role in GVHD is unclear. Here, we retrospectively analyze 228 consecutive patients with malignant diseases undergoing HSCT from 10/10-HLA-matched donors. Low UA levels at the time of HSCT (day 0) were significantly associated with acute GVHD grades II-IV in univariate (HR 0.836, p = 0.0072) and multivariate analyses (HR 0.815, p = 0.0047). There was no significant association between UA levels and overall survival, non-relapse mortality, and relapse. This is the first report demonstrating a negative association between UA levels and acute GVHD. Due to the easy assessment and established pharmaceutical modification of UA, our findings are potentially clinically relevant. Confirmation in independent cohorts and further investigations into underlying mechanisms, such as reduced antioxidative capacity in hypouricemia, are warranted. [ABSTRACT FROM AUTHOR]
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- 2015
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6. Tracking in vivo dynamics of NK cells transferred in patients undergoing stem cell transplantation.
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Killig, Monica, Friedrichs, Birte, Meisig, Johannes, Gentilini, Chiara, Blüthgen, Nils, Loddenkemper, Christoph, Labopin, Myriam, Basara, Nadezda, Pfrepper, Christian, Niederwieser, Dietger W., Uharek, Lutz, and Romagnani, Chiara
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Haploidentical stem cell transplantation (haploSCT) offers an alternative treatment option for advanced leukemia patients lacking a HLA-compatible donor. Transfer of NK cells represents a promising therapeutic option in combination with SCT, as NK cells can promote graft versus leukemia with low risk of GVH disease. In this study, we show results from a phase I/II trial in which 24 acute myeloid leukemia patients underwent haploSCT in combination with early transfer of unmodified NK cells and observed a promising 2-year overall survival rate of 37%. By performing immunomonitoring and subsequent principal component analysis, we tracked donor NK-cell dynamics in the patients and distinguished between NK cells reconstituting from CD34
+ precursors, giving rise over time to a continuum of multiple differentiation stages, and adoptively transferred NK cells. Transferred NK cells displayed a mature phenotype and proliferated in vivo during the early days after haploSCT even in the absence of exogenous IL-2 administration. Moreover, we identified the NK-cell phenotype associated with in vivo expansion. Thus, our study indicates a promising path for adoptive transfer of unmodified NK cells in the treatment of high-risk acute myeloid leukemia. [ABSTRACT FROM AUTHOR]- Published
- 2014
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7. Randomised, double-blind, placebo-controlled trial of oral budesonide for prophylaxis of acute intestinal graft-versus-host disease after allogeneic stem cell transplantation (PROGAST).
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Schmelz, Renate, Bornhäuser, Martin, Schetelig, Johannes, Kiani, Alexander, Platzbecker, Uwe, Schwanebeck, Uta, Grählert, Xina, Uharek, Lutz, Aust, Daniela, Baretton, Gustavo, Schwerdtfeger, Rainer, Hampe, Jochen, Greinwald, Roland, Mueller, Ralph, Ehninger, Gerhard, and Miehlke, Stephan
- Abstract
Background: Gastrointestinal graft–versus-host disease (GvHD) is a potentially life-threatening complication after allogeneic stem cell transplantation (SCT). Since therapeutic options are still limited, a prophylactic approach seems to be warranted. Methods: In this randomised, double-blind-phase III trial, we evaluated the efficacy of budesonide in the prophylaxis of acute intestinal GvHD after SCT. The trial was registered at https://clinicaltrials.gov, number NCT00180089. Patients were randomly assigned to receive either 3 mg capsule three times daily oral budesonide or placebo. Budesonide was applied as a capsule with pH-modified release in the terminal ileum. Study medication was administered through day 56, follow-up continued until 12 months after transplantation. If any clinical signs of acute intestinal GvHD appeared, an ileocolonoscopy with biopsy specimens was performed. Results: The crude incidence of histological or clinical stage 3–4 acute intestinal GvHD until day 100 observed in 91 (n =48 budesonide, n =43 placebo) evaluable patients was 12.5% (95% CI 3-22%) under treatment with budesonide and 14% (95% CI 4-25%) under placebo (p = 0.888). Histologic and clinical stage 3–4 intestinal GvHD after 12 months occurred in 17% (95% CI 6-28%) of patients in the budesonide group and 19% (CI 7-32%) in the placebo group (p = 0.853). Although budesonide was tolerated well, we observed a trend towards a higher rate of infectious complications in the study group (47.9% versus 30.2%, p = 0.085). The cumulative incidences at 12 months of intestinal GvHD stage >2 with death as a competing event (budesonide 20.8% vs. placebo 32.6%, p = 0.250) and the cumulative incidence of relapse (budesonide 20.8% vs. placebo 16.3%, p = 0.547) and non-relapse mortality (budesonide 28% (95% CI 15-41%) vs. placebo 30% (95% CI 15-44%), showed no significant difference within the two groups (p = 0.911). The trial closed after 94 patients were enrolled because of slow accrual. Within the limits of the final sample size, we were unable to show any benefit for the addition of budesonide to standard GvHD prophylaxis. Conclusions: Budesonide did not decrease the occurrence of intestinal GvHD in this trial. These results imply most likely that prophylactic administration of budenoside with pH-modified release in the terminal ileum is not effective. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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8. Genetically Modified T Cells for the Treatment of Malignant Disease.
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Wieczorek, Agnieszka and Uharek, Lutz
- Abstract
SummaryThe broaden application of adoptive T-cell transfer has been constrained by the technical abilities to isolate and expand antigen-specific T cells potent to selectively kill tumor cells. With the recent progress in the design and manufacturing of cellular products, T cells used in the treatment of malignant diseases may be regarded as anticancer biopharmaceuticals. Genetical manipulation of T cells has given T cells desired specificity but also enable to tailor their activation and proliferation potential. Here, we summarize the recent developments in genetic engineering of T-cell-based biopharmaceuticals, covering criteria for their clinical application in regard to safety and efficacy. © 2014 S. Karger GmbH, Freiburg [ABSTRACT FROM AUTHOR]
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- 2013
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9. Utilization of TREC and KREC quantification for the monitoring of early T- and B-cell neogenesis in adult patients after allogeneic hematopoietic stem cell transplantation.
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Mensen, Angela, Ochs, Christoph, Stroux, Andrea, Wittenbecher, Friedrich, Szyska, Martin, Imberti, Luisa, Fillatreau, Simon, Uharek, Lutz, Arnold, Renate, Dörken, Bernd, Thiel, Andreas, Scheibenbogen, Carmen, and Il-Kang Na
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T cell receptors ,B cells ,HEMATOPOIETIC stem cell transplantation ,LYMPHOCYTES ,LEUKEMIA treatment ,BONE marrow ,FLOW cytometry - Abstract
Background: After hematopoietic stem cell transplantation (HSCT) T- and B-cell reconstitution from primary lymphoid organs are a prerequisite for an effective early lymphocyte reconstitution and a long-term survival for adult patients suffering from acute leukemia. Here, we asked whether quantification of T cell receptor excision circle, (TREC) and kappa-deleting recombination excision circle (KREC) before and within six month after allogeneic HSCT could be used to measure the thymic and bone marrow outputs in such patients. Methods: We used a duplex real time PCR assay to quantify the absolute copy counts of TREC and KREC, and correlated the data with absolute cell counts of CD3
+ CD4+ T-cell and CD19+ B-cell subsets determined by flow cytometry, respectively. Results: By comparing two recently proposed naïve T cell subsets, CD31+ naive and CD31- naive T cells, we found a better correlation for the CD31+ subset with TREC level post alloHSCT, in line with the assumption that it contained T cells recently derived from the thymus, indicating that TREC levels reflected real thymic de novo production. Transitional as well as naïve B cells highly correlated with KREC levels, which suggested an association of KREC levels with ongoing bone marrow B cell output. CD45RO+ memory T cells and CD27+ memory B cells were significantly less correlated with TREC and KREC recovery, respectively. Conclusion: We conclude that simultaneous TREC/ KREC quantification is as a suitable and practicable method to monitor thymic and bone marrow output post alloHSCT in adult patients diagnosed with acute leukemia. [ABSTRACT FROM AUTHOR]- Published
- 2013
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10. Immunological Aspects of Candida and Aspergillus Systemic Fungal Infections.
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Mueller-Loebnitz, Christoph, Ostermann, Helmut, Franzke, Anke, Loeffler, Juergen, Uharek, Lutz, Topp, Max, and Einsele, Hermann
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CANDIDA ,STEM cell transplantation ,ASPERGILLUS ,GRAFT versus host disease ,MYCOSES ,TOLL-like receptors ,PATIENTS ,DISEASE risk factors - Abstract
Patients with allogeneic stem cell transplantation (SCT) have a high risk of invasive fungal infections (IFIs) even after neutrophil regeneration. Immunological aspects might play a very important role in the IFI development in these patients. Some data are available supporting the identification of high-risk patients with IFI for example patients receiving stem cells from TLR4 haplotype S4 positive donors. Key defense mechanisms against IFI include the activation of neutrophils, the phagocytosis of germinating conidia by dendritic cells, and the fight of the cells of the innate immunity such as monocytes and natural killer cells against germlings and hyphae. Furthermore, immunosuppressive drugs interact with immune effector cells influencing the specific fungal immune defense and antimycotic drugs might interact with immune response. Based on the current knowledge on immunological mechanism in Aspergillus fumigatus, the first approaches of an immunotherapy using human T cells are in development. This might be an option for the future of aspergillosis patients having a poor prognosis with conventional treatment. [ABSTRACT FROM AUTHOR]
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- 2013
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11. Chronic Graft versus Host Disease but not the Intensity of Conditioning has Impact on Survival after Allogeneic Hematopoietic Stem Cell Transplantation for Advanced Hematological Diseases.
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Hilgendorf, Inken, Wolff, Daniel, Nogai, Axel, Kundt, Günther, Hahn, Joachim, Holler, Ernst, Uharek, Lutz, Junghanss, Christian, Leithäuser, Malte, Thiel, Eckhard, Freund, Mathias, and Kahl, Christoph
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- 2012
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12. Final results of a multicenter phase 1 study of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia.
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Wendtner, Clemens-Martin, Hillmen, Peter, Mahadevan, Daruka, Bühler, Andreas, Uharek, Lutz, Coutré, Steven, Frankfurt, Olga, Bloor, Adrian, Bosch, Francesc, Furman, Richard R., Kimby, Eva, Gribben, John G., Gobbi, Marco, Dreisbach, Luke, Hurd, David D., Sekeres, Mikkael A., Ferrajoli, Alessandra, Shah, Sheetal, Zhang, Jennie, and Moutouh-de Parseval, Laure
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LYMPHOCYTIC leukemia ,LEUKEMIA ,FEBRILE neutropenia ,PRELEUKEMIA ,FLUDARABINE ,DRUG therapy ,PATIENTS - Abstract
Based on clinical activity in phase 2 studies, lenalidomide was evaluated in a phase 2/3 study in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Following tumor lysis syndrome (TLS) complications, the protocol was amended to a phase 1 study to identify the maximum tolerated dose-escalation level (MTDEL). Fifty-two heavily pretreated patients, 69% with bulky disease and 48% with high-risk genomic abnormalities, initiated lenalidomide at 2.5 mg/day, with dose escalation until the MTDEL or the maximum assigned dose was attained. Lenalidomide was safely titrated to 20 mg/day; the MTDEL was not reached. Most common grade 3-4 adverse events were neutropenia and thrombocytopenia; TLS was mild and rare. The low starting dose and conservative dose escalation strategy resulted in six partial responders and 30 patients obtaining stable disease. In summary, lenalidomide 2.5 mg/day is a safe starting dose that can be titrated up to 20 mg/day in patients with CLL. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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13. Intrathecal application of donor lymphocytes in leukemic meningeosis after allogeneic stem cell transplantation.
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Neumann, Martin, Blau, Igor, Burmeister, Thomas, Tietze-Buerger, Carola, Blau, Olga, Gerbitz, Armin, Uharek, Lutz, and Thiel, Eckhard
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LYMPHOCYTES ,STEM cell transplantation ,CENTRAL nervous system ,LEUKEMIA ,GRAFT versus host disease ,HEMATOLOGY ,MENINGES - Abstract
Extramedullary relapses after allogeneic stem cell transplantation, especially within the central nervous system (CNS), are not only difficult to treat but also associated with poor outcome. Although the graft-versus-leukemia (GvL) effect is nowadays accepted and well documented, it remains controversial whether one can make use of GvL effects in immunological-restricted areas ('sanctuary sites') like the central nervous system. Here, we present data of three hematological patients suffering from isolated CNS relapse of CML or AML after allogeneic stem cell transplantation. Patients received in addition to chemotherapy intrathecal infusions of donor lymphocytes by CD14 depletion of peripheral blood mononuclear cells from the correspondent allogeneic donor. Referring to an observation period of maximum 17 months no immediate or delayed side effects could be detected. [ABSTRACT FROM AUTHOR]
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- 2011
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14. MyD88/TLR9 mediated immunopathology and gut microbiota dynamics in a novel murine model of intestinal graft-versus-host disease.
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Heimesaat, Markus M., Nogai, Axel, Bereswill, Stefan, Plickert, Rita, Fischer, André, Loddenkemper, Christoph, Steinhoff, Ulrich, Tchaptchet, Sandrine, Thiel, Eckhard, Freudenberg, Marina A., Göbel, Ulf B., and Uharek, Lutz
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BACTERIA ,GRAFT versus host disease ,STEM cell transplantation ,GASTROINTESTINAL system ,IMMUNOPATHOLOGY ,LABORATORY mice ,APOPTOSIS ,OLIGONUCLEOTIDES - Abstract
BACKGROUND: The bacterial microflora aggravates graft-versus-host-disease (GvHD) after allogeneic stem cell transplantation, but the underlying mechanisms of manifestations of intestinal GvHD (iGvHD) in the gut remain poorly understood. AIM: To analyse the gut flora composition and the impact of bacterial sensing via Toll-like receptors (TLRs) in iGvHD. METHODS: By mimicking clinical low-intensity conditioning regimens used in humans, a novel irradiation independent, treosulfan and cyclophosphamide-based murine allogeneic transplantation model was established. A global survey of the intestinal microflora by cultural and molecular methods was performed, the intestinal immunopathology in TLR-deficient recipient mice with iGvHD investigated and finally, the impact of anti-TLR9 treatment on iGvHD development assessed. RESULTS: The inflammatory responses in iGvHD were accompanied by gut flora shifts towards enterobacteria, enterococci and Bacteroides/Prevotella spp. Analysis of iGvHD in MyD88-/-, TRIF-/-, TLR2/4-/-, and TLR9-/-recipient mice showed that bacterial sensing via TLRs was essential for iGvHD development. Acute iGvHD was characterised by increasing numbers of apoptotic cells, proliferating cells, T cells and neutrophils within the colon. These responses were significantly reduced in MyD88-/-, TLR2/4-/-, TRIF-/-and TLR9-/-mice, as compared with wild-type controls. However, TRIF-/-and TLR2/4-/-mice were not protected from mortality, whereas TLR9-/-mice displayed increased survival rates. The important role of TLR9-mediated immunopathology was independently confirmed by significantly reduced macroscopic disease symptoms and colonic apoptosis as well as by reduced T-cell and neutrophil numbers within the colon after treatment with a synthetic inhibitory oligonucleotide. CONCLUSIONS: These results emphasise the critical role of gut microbiota, innate immunity and TLR9 in iGvHD and highlight anti-TLR9 strategies as novel therapeutic options. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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15. Central nervous system infections in immunocompromised patients - update on diagnostics and therapy.
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Schmidt-Hieber MD, Martin, Zweigner, Janine, Uharek, Lutz, Blau, Igor W., and Thiel, Eckhard
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CENTRAL nervous system infections ,HERPESVIRUS diseases ,GRAFT versus host disease ,VIRAL disease diagnosis ,TUMORS ,CRYPTOGAMS - Abstract
Infections of the central nervous system (CNS) are increasingly reported in patients with malignancies. Heavily immunocompromised patients like those after allogeneic stem cell transplantation (SCT) or previous T cell depleting treatment regimens (e.g. with fludarabine or alemtuzumab) are at highest risk for cerebral infections. The spectrum of causative organisms may vary greatly, depending on the underlying malignancy, its treatment and various other factors. Toxoplasma gondii and fungi are the leading causative organisms in patients after allogeneic SCT, but also viruses such as herpes simplex virus or JC virus may be detected in these patients. Definitive diagnosis of cerebral infection still remains a high challenge, although diagnostics have improved by the wide availability of imaging techniques and polymerase chain reaction in recent years. Novel therapeutic options are arising, particularly for fungal CNS infections. Here, we summarise aspects on epidemiology, clinical symptoms and prognosis of CNS infections in patients with malignancies. Additionally, we give an overview on the diagnostics and management of cerebral infections in these patients including evidence evaluation of efficacy of treatment. [ABSTRACT FROM AUTHOR]
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- 2009
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16. Biocompatible porous ceramics for the cultivation of hematopoietic cells.
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Berthold, Almuth, Haibel, Astrid, Brandes, Natascha, Kroh, Lothar, Gross, Ulrich, Uharek, Lutz, and Schubert, Helmut
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CERAMIC materials ,POROSITY ,SERUM albumin ,BLOOD proteins ,CELL lines ,ALUMINUM oxide ,BLOOD plasma - Abstract
Porous ceramics made of alumina and hydroxyapatite were created using a protein foaming method. Porosity and pore size distribution were successfully varied by means of chemical modification of the foaming protein Bovine serum albumin (BSA). The effectiveness of the BSA and of its chemical modifications as well as the influence of the dispersing agent were investigated using synchrotron tomography. Resulting porous ceramic materials were used as three-dimensional substrates for the cultivation of human peripheral stem cells. The cells proliferated and differentiated in culture. Five cell lines consistent with human blood cell lines were observed. [ABSTRACT FROM AUTHOR]
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- 2007
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17. Efficacy of the interleukin-2 receptor antagonist basiliximab in steroid-refractory acute graft- versus-host disease.
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Schmidt-Hieber, Martin, Fietz, Thomas, Knauf, Wolfgang, Uharek, Lutz, Hopfenmüller, Werner, Thiel, Eckhard, and Blau, Igor Wolfgang
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INTERLEUKIN-2 ,STEM cell transplantation ,GRAFT versus host disease ,TRANSPLANTATION of organs, tissues, etc. ,CELL transplantation ,HEMATOLOGY - Abstract
Acute graft- versus-host disease (aGVHD) occurs in up to 80% of patients who undergo allogeneic stem cell transplantation (SCT) and contributes significantly to transplant-related mortality (TRM). We conducted a prospective phase II trial to assess the efficacy and feasibility of treating steroid-refractory aGVHD with basiliximab, a chimaeric monoclonal antibody directed against the alpha chain of the interleukin-2 (IL-2) receptor. Basiliximab was administered intravenously at a dose of 20 mg on days 1 and 4. Twenty-three patients were enrolled between October 1999 and July 2004. We found a primary overall response rate of 82·5% with four patients (17·5%) showing a complete response and 15 patients (65%) a partial response. Six patients were again treated successfully with an IL-2 receptor antagonist because of recurrence of aGVHD. The rates of infections, chronic GVHD, malignancy recurrence and 1-year TRM following immunosuppression with basiliximab were comparable with those found with other treatment modalities for aGVHD. We conclude that basiliximab is efficient and feasible for steroid-refractory aGVHD and merits further evaluation. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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18. Therapeutic effects of idiotype vaccination can be enhanced by the combination of granulocyte–macrophage colony-stimulating factor and interleukin 2 in a myeloma model.
- Author
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Stritzke, Jan, Zunkel, Tim, Steinmann, Jörg, Schmitz, Norbert, Uharek, Lutz, and Zeis, Matthias
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B cell lymphoma ,ANTI-idiotypic vaccines ,TUMOR treatment - Abstract
Summary. Idiotype (Id) vaccination provides an interesting immunotherapeutic strategy against B-cell lymphomas. In multiple myeloma (MM), however, the therapeutic efficacy of Id vaccination has been disappointing. In an attempt to improve the antitumoral potential, we added granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 2 (IL-2) to the protocol. Balb/c mice were inoculated i.p. (d 2) with different doses (1–5 × 10
5 ) of HOPC myeloma cells secreting the IgHOPC Id protein. Two days later, animals were injected with 10 000 U GM-CSF i.p. for 6 d consecutively (d 0–5). On d 5 and 11, myeloma-specific immunoglobulin (IgHOPC ) was administered i.p. together with incomplete Freund adjuvans followed by IL-2 (2 × 10 000 U/d; i.p) for 10 d (d 5–14). In animals inoculated with 105 myeloma cells, treatment with IL-2 given as a single agent prolonged the median survival time (MST, 67 d) when compared with the tumour control group (MST 48 d), whereas GM-CSF did not elicit any survival benefit (MST 49 d). Complete tumour rejection could be achieved in 27% (4/15) by the combination of Id vaccination and GM-CSF. Additional treatment with IL-2 further increased antimyeloma activity. In this case, 59% of the animals showed no signs of tumour recurrence. In mice with high tumour burden (5 × 105 ), no treatment modality achieved long-term survivors. Both natural killer (NK) cells and CD8+ T cells may be involved in the antitumoural immune response. These data provide evidence for the combined use of GM-CSF and IL-2 to enhance the therapeutic effectiveness of clinical cancer vaccination protocols. [ABSTRACT FROM AUTHOR]- Published
- 2003
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19. Enhanced antitumoral effectiveness of idiotype vaccination induced by the administration of Flt3 ligand combined with interleukin 2 against a murine myeloma.
- Author
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Zeis, Matthias, Zunkel, Tim, Steinmann, Jörg, Schmitz, Norbert, and Uharek, Lutz
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MULTIPLE myeloma ,ANTI-idiotypic vaccines ,LIGANDS (Biochemistry) - Abstract
Summary. Idiotype (Id) vaccination provides an innovative treatment modality against B-cell malignancies. In multiple myeloma patients, however, the antitumoral potential of this immunotherapeutic concept is limited. In an attempt to improve the therapeutic effectiveness of Id vaccination, we added Flt3 ligand (Flt3-L) and interleukin 2 (IL-2) to the protocol. Balb/c mice were inoculated i.p. (d -2) with different doses (1–5 × 10
5 ) of HOPC myeloma cells, secreting the IgHOPC Id-protein. Two days later, animals were treated with Flt3-L (10 µg per mouse/d, given i.p) for 10 consecutive days (d 0–9). On d 5 and d 11, myeloma-specific immunoglobulin (IgHOPC ) was administered s.c., together with incomplete Freund adjuvans (IFA) followed by the administration of IL-2 (2 × 10·000/d given i.p) for 10 d (d 5–14). Whereas IgHOPC , Flt3-L or IL-2, given alone, did not elicit long-term survival, the combination of IL-2 or Flt3-L with Id vaccination achieved a complete tumour rejection in 27% and 41% of mice respectively. However, the most powerful antimyeloma effects were induced by Flt3-L + Id vaccination + IL-2: 81% of the treated animals experienced long-term survival (> 180 d). Both natural killer (NK) cells and CD8+ T cells may be involved in the antitumoral immune response. These data suggest that the combination of Flt3-L and IL-2 can be used to enhance the therapeutic effectiveness of clinical cancer vaccination protocols. [ABSTRACT FROM AUTHOR]- Published
- 2002
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20. Activation of natural killer cells with interleukin 2 (IL-2) and IL-12 increases perforin binding and subsequent lysis of tumour cells.
- Author
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Lehmann, Christof, Zeis, Matthias, and Uharek, Lutz
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KILLER cells ,INTERLEUKIN-2 ,INTERLEUKIN-12 ,CANCER cells - Abstract
Natural killer (NK) cells can lyse a variety of different tumour cells by exocytosis of perforin, subsequent binding of perforin to the target cell membrane and formation of lytic pores. Some tumour cells, however, are resistant to cellular cytotoxicity. Using the NK-resistant tumour cell lines ML-2, MONOMAC-1, RPMI and L540Cy, we demonstrated that activation of NK cells with interleukin 2 (IL-2) and IL-12 resulted in significant lysis of these tumour targets. To investigate the underlying mechanisms, we isolated the cytotoxic granules from non-activated and IL-2-/IL-12-activated NK cells and compared the killing of K562 leukaemia cells (sensitive to NK cell-mediated lysis) and ML-2 leukaemia cells (resistant to NK cell-mediated lysis). In contrast to K562 cells, which were easily killed by NK-cell granules, ML-2 cells were resistant to granules from non-activated NK cells. However, granules from NK cells activated with IL-2 and IL-12 were able to induce significant tumour cell lysis. Cell death of both K562 and ML-2 cells by granules from activated NK cells was completely blocked by anti-perforin antibodies, indicating that perforin mainly accounts for the lysis induced by NK granules. Comparing granules from non-activated and IL-2-/IL-12-activated NK cells, the increased cell death of ML-2 cells was caused by an improved binding of perforin to the target cell membrane. Functional assays, however, indicated that the differences in perforin binding were not as a result of an augmented production of perforin by activated NK cells. We conclude that activation of NK cells results in an increased binding of perforin and subsequent lysis of tumour cells. [ABSTRACT FROM AUTHOR]
- Published
- 2001
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21. Graft-versus-leukaemia activity can be predicted by natural cytotoxicity against leukaemia cells.
- Author
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Glass, Bertram, Uharek, Lutz, Zeis, Matthias, Loeffler, Helmut, Mueller-Ruchholtz, Wolfgang, and Gassmann, Winifried
- Published
- 1996
- Full Text
- View/download PDF
22. MHC-Associated and MHC-lndependent Urinary Chemosignals in Mice Are Expressed via the Hematopoietic System.
- Author
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Eggert, Frank, Uharek, Lutz, Müller-Ruchholtz, Wolfgang, and Ferstl, Roman
- Published
- 1994
- Full Text
- View/download PDF
23. The Hematopoietic System Influences Odor Specificity in Mice and Rats.
- Author
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Eggert, Frank, Uharek, Lutz, Müller-Ruchhollz, Wolfgang, and Ferstl, Roman
- Published
- 1993
- Full Text
- View/download PDF
24. ALLOGENEIC NK CELLS AS POTENT ANTILEUKEMIC EFFECTOR CELLS AFTER ALLOGENEIC BONE MARROW TRANSPLANTATION IN MICE.
- Author
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Zeis, Matthias, Uharek, Lutz, Glass, Bertram, Gaska, Tobias, Steinmann, Jörg, Gassmann, Winfried, Löffler, Helmut, and Müller-Rchholtz, Wolfgang
- Published
- 1995
- Full Text
- View/download PDF
25. DEGRANULATION OF T CELLS SPECIFIC FOR HUMAN CYTOMEGALOVIRUS (CMV) PROTEINS PP65 AND IE1 IS NOT DISTURBED IN TRANSPLANT PATIENTS.
- Author
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Fuhrmann, Stephan, Lehmkuhl, Hans, Hetzer, Roland, Uharek, Lutz, Volk, Hans-Dieter, Reinke, Petra, and Kern, Florian
- Published
- 2006
26. Randomised, double-blind, placebo-controlled trial of oral budesonide for prophylaxis of acute intestinal graft-versus-host disease after allogeneic stem cell transplantation (PROGAST).
- Author
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Schmelz, Renate, Bornhäuser, Martin, Schetelig, Johannes, Kiani, Alexander, Platzbecker, Uwe, Schwanebeck, Uta, Grählert, Xina, Uharek, Lutz, Aust, Daniela, Baretton, Gustavo, Schwerdtfeger, Rainer, Hampe, Jochen, Greinwald, Roland, Mueller, Ralph, Ehninger, Gerhard, and Miehlke, Stephan
- Abstract
Background: Gastrointestinal graft-versus-host disease (GvHD) is a potentially life-threatening complication after allogeneic stem cell transplantation (SCT). Since therapeutic options are still limited, a prophylactic approach seems to be warranted.Methods: In this randomised, double-blind-phase III trial, we evaluated the efficacy of budesonide in the prophylaxis of acute intestinal GvHD after SCT. The trial was registered at https://clinicaltrials.gov, number NCT00180089.Results: The crude incidence of histological or clinical stage 3-4 acute intestinal GvHD until day 100 observed in 91 (n =48 budesonide, n =43 placebo) evaluable patients was 12.5% (95% CI 3-22%) under treatment with budesonide and 14% (95% CI 4-25%) under placebo (p = 0.888). Histologic and clinical stage 3-4 intestinal GvHD after 12 months occurred in 17% (95% CI 6-28%) of patients in the budesonide group and 19% (CI 7-32%) in the placebo group (p = 0.853). Although budesonide was tolerated well, we observed a trend towards a higher rate of infectious complications in the study group (47.9% versus 30.2%, p = 0.085). The cumulative incidences at 12 months of intestinal GvHD stage >2 with death as a competing event (budesonide 20.8% vs. placebo 32.6%, p = 0.250) and the cumulative incidence of relapse (budesonide 20.8% vs. placebo 16.3%, p = 0.547) and non-relapse mortality (budesonide 28% (95% CI 15-41%) vs. placebo 30% (95% CI 15-44%), showed no significant difference within the two groups (p = 0.911). The trial closed after 94 patients were enrolled because of slow accrual. Within the limits of the final sample size, we were unable to show any benefit for the addition of budesonide to standard GvHD prophylaxis.Conclusions: Budesonide did not decrease the occurrence of intestinal GvHD in this trial. These results imply most likely that prophylactic administration of budenoside with pH-modified release in the terminal ileum is not effective. [ABSTRACT FROM AUTHOR]- Published
- 2014
- Full Text
- View/download PDF
27. Adoptive antifungal T cell immunotherapy -- into the clinic?
- Author
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Lehrnbecher, Thomas, Schmidt, Stanislaw, Koehl, Ulrike, Schuster, Friedhelm R., Uharek, Lutz, Klingebiel, Thomas, and Tramsen, Lars
- Abstract
The morbidity and mortality rates of invasive fungal infection in allogeneic stem cell recipients are still unacceptably high and have not been significantly improved by alternative antifungal strategies to date. Over the last few years, rapid methods for the clinical-scale generation of functionally active and well characterized antifungal T
H 1 cells have become available. In addition, current data on the use of donor-derived virus-specific T cells in allogeneic stem cell transplantation suggest that the risk of severe adverse events, in particular the risk of graft-versus-host disease, is negligible. Therefore, adoptive antifungal immunotherapeutic strategies should be evaluated in clinical trials. However, one has to recognize that these trials are only meaningful with sufficiently large and homogenous cohorts of patients and if the settings of adoptive antifungal immunotherapy are comparable. Ultimately, the strategy of adoptively transferring antifungal immune responses might improve the outcome in hematopoietic stem cell recipients suffering from invasive fungal infection. [ABSTRACT FROM AUTHOR]- Published
- 2011
- Full Text
- View/download PDF
28. Air embolism simulating atypical pneumonia.
- Author
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Penack, Olaf, Wolf, Karl-Jürgen, and Uharek, Lutz
- Subjects
STEM cell transplantation ,ACUTE myeloid leukemia ,EMBOLISMS ,LUNG diseases ,PNEUMONIA - Abstract
Presents the case of an 18-year-old man who was admitted for allogeneic stem cell transplantation in first remission of acute myeloid leukemia. Physical examination of a patient which reveals air embolism due to an open lid of the jugular vein central line; Use of computed tomography in identifying cause and nature of the disease; Discharge of patient from hospital after the transplantation.
- Published
- 2005
- Full Text
- View/download PDF
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