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3. Efficient non-viral T cell engineering for TCR gene therapy by Sleeping Beauty minicircles

Author

Uckert, Wolfgang, Matuschewski, Kai, Pezzutto, Antonio, Clauß, Julian, Uckert, Wolfgang, Matuschewski, Kai, Pezzutto, Antonio, and Clauß, Julian

Abstract

Sleeping Beauty (SB) Transposon-basierte Vektoren werden als Alternative zu viralen Vektoren für T-Zell-Gentherapie erforscht und ermöglichen eine schnelle und kostengünstige Genmanipulation von T-Zellen. Die Verwendung von Transposon-Vektoren erfordert jedoch die DNA-Elektroporation von T-Zellen, die sich schädlich auf T-Zellen auswirkt. DNA-elektroporierte T-Zellen weisen eine verringerte Lebensfähigkeit und eine verzögerte Aktivierung nach Stimulation des T-Zell-Rezeptors (TCR) auf. Um die Nachteile der Transposon-basierten T-Zell-Genmanipulation zu überwinden, haben wir neuartige SB-Vektoren entwickelt. Durch die Kombination von SB Transposon-basierten Minicircle-Vektoren mit SB100X Transposase-mRNA konnten T-Zellen effizient genmodifiziert werden. Unser Ansatz reduzierte die T-Zell-Mortalität und steigerte gleichzeitig die Transfektionseffizienz. Mit diesen neuartigen Vektoren wurde die stabile Expression verschiedener TCRs und CARs in über 50% der eingesetzten T-Zellen erreicht. Gentechnisch manipulierte T-Zellen konnten Antigen-spezifisch stimuliert werden und zeigten effiziente Zytokin-Sekretion und Tumorzell-Lyse. Weiterhin haben wir miRNAs entwickelt, die die Expression der endogenen TCR-Ketten unterdrücken. Der Einbau dieser miRNAs in die TCR-Expressionskassette erhöhte die Oberflächenexpression des therapeutischen TCRs, verringerte die Fehlpaarung mit endogenen TCR-Ketten und erhöhte die T-Zell-Funktionalität. Ein direkter Vergleich von SB- und Virus-modifizierten T-Zellen zeigte sowohl in vitro als auch in vivo eine vergleichbare Wirksamkeit der modifizierten T-Zellen hinsichtlich Zytokin-Sekretion, Tumorzell-Lyse und Tumorkontrolle. In dieser Arbeit konnte gezeigt werden, dass SB Minicircle-Vektoren die Herstellung von genetisch modifizierten T-Zellen ermöglichen und diese Tumor-spezifische Wirksamkeit aufweisen. Dieser Ansatz könnte die Herstellung therapeutischer T-Zellen für die personalisierte T-Zell-Gentherapie vereinfachen und beschleunigen., Sleeping Beauty (SB) transposon-based vectors have entered clinical trials as an alternative to viral vectors for T cell gene therapy, offering time- and cost-efficient engineering of therapeutic T cells. However, transposon vectors require DNA electroporation into T cells, which we found to cause adverse effects. T cell viability was decreased, and DNA-transfected T cells showed delayed activation upon T cell receptor (TCR) stimulation regarding blast formation and proliferation. To overcome the limitations of transposon-based T cell engineering, we investigated the effect of DNA electroporation on T cells and developed novel SB vectors. T cells could efficiently be engineered with Sleeping Beauty vectors by combining SB transposon minicircles and SB100X transposase mRNA. Our approach reduced T cell mortality and substantially enhanced transfection efficiency. We achieved stable expression of several TCRs and CARs in more than 50% of the transfected T cells compared to 15% when conventional plasmids were used. T cells engineered to express a tumor-specific TCR mediated effective tumor cell lysis and cytokine secretion upon antigen-specific stimulation. Furthermore, we developed miRNAs to silence the expression of the endogenous TCR chains. Incorporation of these miRNAs into the TCR expression cassette increased surface expression of the therapeutic TCR, diminished mispairing with endogenous TCR chains, and enhanced T cell functionality. Importantly, a direct comparison of SB minicircle- and RV-engineered T cells in vitro as well as in vivo demonstrated equal T cell efficacy with regards to cytokine release, tumor cell lysis and tumor control. We demonstrated that SB minicircles enable the generation of gene-modified T cells with tumor-specific reactivity. Our approach facilitates the manufacturing of therapeutic T cells with superior biosafety and accelerates the generation of patient-specific T cell products for personalized T cell gene therapy.

Published
2023

4. Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML Study IV

Author

Saußele, Susanne, Krauß, Marie-Paloma, Hehlmann, Rüdiger, Lauseker, Michael, Proetel, Ulrike, Kalmanti, Lida, Hanfstein, Benjamin, Fabarius, Alice, Kraemer, Doris, Berdel, Wolfgang E., Bentz, Martin, Staib, Peter, de Wit, Maike, Wernli, Martin, Zettl, Florian, Hebart, Holger F., Hahn, Markus, Heymanns, Jochen, Schmidt-Wolf, Ingo, Schmitz, Norbert, Eckart, Michael J., Gassmann, Winfried, Bartholomäus, Andrea, Pezzutto, Antonio, Leibundgut, Elisabeth Oppliger, Heim, Dominik, Krause, Stefan W., Burchert, Andreas, Hofmann, Wolf-Karsten, Hasford, Joerg, Hochhaus, Andreas, Pfirrmann, Markus, and Müller, Martin C.

Published
2015
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5. Alemtuzumab plus CHOP versus CHOP in elderly patients with peripheral T-cell lymphoma: the DSHNHL2006-1B/ACT-2 trial

Author

Wulf, Gerald G, Altmann, Bettina, Ziepert, Marita, D'Amore, Francesco, Held, Gerhard, Greil, Richard, Tournilhac, Olivier, Relander, Thomas, Viardot, Andreas, Wilhelm, Martin, Wilhelm, Christian, Pezzutto, Antonio, Zijlstra, Josee M, Van Den Neste, Eric, Lugtenburg, Pieternella J, Doorduijn, Jeanette K, Gelder, Michel van, van Imhoff, Gustaaf W, Zettl, Florian, Braulke, Friederike, Nickelsen, Maike, Glass, Bertram, Rosenwald, Andreas, Gaulard, Philippe, Loeffler, Markus, Pfreundschuh, Michael, Schmitz, Norbert, Trümper, Lorenz, ACT-2 study investigators, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, UCL - (SLuc) Service d'hématologie, UCL - (SLuc) Centre du cancer, Hematology, CCA - Cancer Treatment and quality of life, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne (UCA), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Interne Geneeskunde, and MUMC+: MA Hematologie (9)

Subjects
0301 basic medicine, Male, cd52 expression, Cancer Research, epstein-barr-virus, medicine.medical_treatment, CHOP, Gastroenterology, PROPHYLAXIS, 0302 clinical medicine, Cause of Death, Antineoplastic Combined Chemotherapy Protocols, Medicine, Significant risk, Alemtuzumab, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, Hematology, lymphoproliferative disorders, Hazard ratio, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Middle Aged, CHEMOTHERAPY, Prognosis, 3. Good health, Treatment Outcome, Oncology, Vincristine, 030220 oncology & carcinogenesis, Toxicity, PHASE-II, Female, medicine.drug, medicine.medical_specialty, prognostic-factors, Medication Adherence, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, Humans, non-hodgkin-lymphoma, Cyclophosphamide, Aged, Chemotherapy, therapy, business.industry, Lymphoma, T-Cell, Peripheral, DETUDE-DES-LYMPHOMES, medicine.disease, Survival Analysis, Peripheral T-cell lymphoma, 030104 developmental biology, Doxorubicin, Prednisone, business
Abstract

PTCL patients exhibit poor survival with existing treatments. We investigated the efficacy of CHOP combined with alemtuzumab in 116 PTCL patients age 61–80 in an open-label, randomized phase 3 trial. Alemtuzumab was given on day 1, to a total of 360 mg in 21 patients, or 120 mg in 37. Hematotoxicity was increased with A-CHOP resulting in more grade ≥3 infections (40% versus 21%) and 4 versus 1 death due to infections, respectively. CR/CRu rate was 60% for A-CHOP and 43% for CHOP, and OR rate was 72% and 66%, respectively. Three-year-EFS, PFS and OS were 27% [15%–39%], 28% [15%–40%], and 37% ([23%–50%] for A-CHOP, and 24% [12%–35%], 29% [17%–41%], and 56% [44%–69%] for CHOP, respectively, showing no significant differences. Multivariate analyses, adjusted for strata and sex confirmed these results (hazard ratio HREFS: 0.7 ([95% CI: 0.5–1.1]; p = 0.094), HRPFS: 0.8 ([95% CI: 0.5–1.2]; p = 0.271), HROS: 1.4 ([95% CI: 0.9–2.4]; p = 0.154). The IPI score was validated, and male sex (HREFS 2.5) and bulky disease (HREFS 2.2) were significant risk factors for EFS, PFS, and OS. Alemtuzumab added to CHOP increased response rates, but did not improve survival due to treatment-related toxicity.

Published
2021

7. High Immune Response Rates and Decreased Frequencies of Regulatory T Cells in Metastatic Renal Cell Carcinoma Patients after Tumor Cell Vaccination

Author

Pohla, Heike, Buchner, Alexander, Stadlbauer, Birgit, Frankenberger, Bernhard, Stevanovic, Stefan, Walter, Steffen, Frank, Ronald, Schwachula, Tim, Olek, Sven, Kopp, Joachim, Willimsky, Gerald, Stief, Christian G, Hofstetter, Alfons, Pezzutto, Antonio, Blankenstein, Thomas, Oberneder, Ralph, and Schendel, Dolores J

Published
2012
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9. Alemtuzumab plus CHOP versus CHOP in elderly patients with peripheral T-cell lymphoma: the DSHNHL2006-1B/ACT-2 trial.

Author

UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, UCL - (SLuc) Service d'hématologie, UCL - (SLuc) Centre du cancer, Wulf, Gerald G, Altmann, Bettina, Ziepert, Marita, D'Amore, Francesco, Held, Gerhard, Greil, Richard, Tournilhac, Olivier, Relander, Thomas, Viardot, Andreas, Wilhelm, Martin, Wilhelm, Christian, Pezzutto, Antonio, Zijlstra, Josee M, Van Den Neste, Eric, Lugtenburg, Pieternella J, Doorduijn, Jeanette K, Gelder, Michel van, van Imhoff, Gustaaf W, Zettl, Florian, Braulke, Friederike, Nickelsen, Maike, Glass, Bertram, Rosenwald, Andreas, Gaulard, Philippe, Loeffler, Markus, Pfreundschuh, Michael, Schmitz, Norbert, Trümper, Lorenz, ACT-2 study investigators, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, UCL - (SLuc) Service d'hématologie, UCL - (SLuc) Centre du cancer, Wulf, Gerald G, Altmann, Bettina, Ziepert, Marita, D'Amore, Francesco, Held, Gerhard, Greil, Richard, Tournilhac, Olivier, Relander, Thomas, Viardot, Andreas, Wilhelm, Martin, Wilhelm, Christian, Pezzutto, Antonio, Zijlstra, Josee M, Van Den Neste, Eric, Lugtenburg, Pieternella J, Doorduijn, Jeanette K, Gelder, Michel van, van Imhoff, Gustaaf W, Zettl, Florian, Braulke, Friederike, Nickelsen, Maike, Glass, Bertram, Rosenwald, Andreas, Gaulard, Philippe, Loeffler, Markus, Pfreundschuh, Michael, Schmitz, Norbert, Trümper, Lorenz, and ACT-2 study investigators

Abstract

PTCL patients exhibit poor survival with existing treatments. We investigated the efficacy of CHOP combined with alemtuzumab in 116 PTCL patients age 61-80 in an open-label, randomized phase 3 trial. Alemtuzumab was given on day 1, to a total of 360 mg in 21 patients, or 120 mg in 37. Hematotoxicity was increased with A-CHOP resulting in more grade ≥3 infections (40% versus 21%) and 4 versus 1 death due to infections, respectively. CR/CRu rate was 60% for A-CHOP and 43% for CHOP, and OR rate was 72% and 66%, respectively. Three-year-EFS, PFS and OS were 27% [15%-39%], 28% [15%-40%], and 37% ([23%-50%] for A-CHOP, and 24% [12%-35%], 29% [17%-41%], and 56% [44%-69%] for CHOP, respectively, showing no significant differences. Multivariate analyses, adjusted for strata and sex confirmed these results (hazard ratio HR: 0.7 ([95% CI: 0.5-1.1]; p = 0.094), HR: 0.8 ([95% CI: 0.5-1.2]; p = 0.271), HR: 1.4 ([95% CI: 0.9-2.4]; p = 0.154). The IPI score was validated, and male sex (HR 2.5) and bulky disease (HR 2.2) were significant risk factors for EFS, PFS, and OS. Alemtuzumab added to CHOP increased response rates, but did not improve survival due to treatment-related toxicity.

Published
2021

10. Spontaneous Non-Sustained Ventricular Tachycardia and Premature Ventricular Contractions and Their Prognostic Relevance in Patients with Cancer in Routine Care

Author

Albrecht, Annemarie, primary, Porthun, Jan, additional, Eucker, Jan, additional, Coats, Andrew, additional, von Haehling, Stephan, additional, Pezzutto, Antonio, additional, Karakas, Mahir, additional, Riess, Hanno, additional, Keller, Ulrich, additional, Landmesser, Ulf, additional, Haverkamp, Wilhelm, additional, Anker, Stefan, additional, and Anker, Markus, additional

Published
2021
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16. Successful long-term monotherapy with rituximab in a patient with chronic lymphocytic leukemia of the B-cell-lineage: a case report

Author

Sturm Isrid, Oertel Joachim, Oertel Stephan, Westermann Jörg, and Pezzutto Antonio

Subjects
Medicine
Abstract

Abstract Introduction Treatment of chronic lymphocytic leukemia of the B-cell-lineage is strongly based upon clinical staging because of the heterogeneous clinical course of this disease. Case presentation We describe a 62-year-old patient with newly diagnosed chronic lymphocytic leukemia of the B-cell-lineage who did not respond to several chemotherapy regimens including chlorambucil, fludarabine and cyclophosphamide, developing a marked neutropenia and thrombocytopenia with life-threatening infections. Further chemotherapy appeared not feasible because of bone marrow toxicity. The patient was treated with 600 mg/m2 rituximab weekly followed by eight courses of biweekly therapy and then by long-term maintenance therapy, achieving almost complete remission of the symptoms and disease control. Conclusion After resistance to standard chemotherapy with chlorambucil and fludarabine, a patient with chronic lymphocytic leukemia of the B-cell-lineage was successfully treated with rituximab.

Published
2008
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17. Final Analysis of the Front-Line Phase III Randomized ACT-1 Trial in Younger Patients with Systemic Peripheral T-Cell Lymphoma Treated with CHOP Chemotherapy with or without Alemtuzumab and Consolidated By Autologous Hematopoietic Stem Cell Transplant

Author

d'Amore, Francesco, primary, Leppä, Sirpa, additional, Silva, Maria Gomes da, additional, Relander, Thomas, additional, Lauritzsen, Grete Fossum, additional, Brown, Peter De Nully, additional, Pezzutto, Antonio, additional, Doorduijn, Jeanette K., additional, Weidmann, Eckhart, additional, van Gelder, Michel, additional, Hoof, Achiel Van, additional, Christiansen, Ilse, additional, Fagerli, Unn Merete, additional, Hagberg, Hans, additional, Lugtenburg, P.J., additional, Walewski, Jan, additional, Wu, Ka Lung, additional, Demuynck, Hilde Maria, additional, Fijnheer, Rob, additional, Christensen, Jacob H., additional, Jankovská, Milada, additional, Josefsson, Pär L., additional, Kluin-Nelemans, Hanneke, additional, Mariz, Jose Mario, additional, Merup, Mats A., additional, Noesslinger, Thomas, additional, Van Den Neste, Eric, additional, Zijlstra, Josée M, additional, Hopfinger, Georg, additional, Prochazka, VIT, additional, Jantunen, Esa, additional, Boudova, Ludmila, additional, Cabecadas, Jose, additional, Chott, Andreas, additional, Delabie, Jan M.A., additional, de Leval, Laurence, additional, Diepstra, Arjan, additional, Karjalainen-Lindsberg, Marja-Liisa, additional, Noergaard, Peter, additional, Rosenwald, Andreas, additional, Rymkiewicz, Grzegorz, additional, Sundström, Christer, additional, Truemper, Lorenz, additional, Wulf, Gerald, additional, Chong, Lauren, additional, Bouska, Alyssa, additional, Smith, Lynette, additional, Gisselbrecht, Christian, additional, Ziepert, Marita, additional, Loeffler, Markus, additional, Liestol, Knut, additional, Steidl, Christian, additional, Gascoyne, Randy D., additional, Scott, David W., additional, Altmann, Bettina, additional, Iqbal, Javeed, additional, Chan, Wing C, additional, and Toldbod, Helle, additional

Published
2018
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18. Final Evaluation of Randomized CML-Study IV: 10-Year Survival and Evolution of Terminal Phase

Author

Hehlmann, Rüdiger, primary, Lauseker, Michael, additional, Saussele, Susanne, additional, Pfirrmann, Markus, additional, Krause, Stefan W., additional, Kolb, Hans-Jochem, additional, Neubauer, Andreas, additional, Hossfeld, Dieter K., additional, Nerl, Christoph, additional, Gratwohl, Alois, additional, Baerlocher, Gabriela M., additional, Heim, Dominik, additional, Bruemmendorf, Tim Henrik, additional, Fabarius, Alice, additional, Haferlach, Claudia, additional, Schlegelberger, Brigitte, additional, Müller, Martin C., additional, Jeromin, Sabine, additional, Proetel, Ulrike, additional, Kohlbrenner, Katharina, additional, Voskanyan, Astghik, additional, Rinaldetti, Sébastien, additional, Seifarth, Wolfgang, additional, Spiess, Birgit, additional, Balleisen, Leopold, additional, Goebeler, Maria E, additional, Hänel, Mathias, additional, Ho, Anthony D., additional, Dengler, J, additional, Falge, C, additional, Kanz, Lothar, additional, Köhne, Claus-Henning, additional, Burchert, Andreas, additional, Kneba, Michael, additional, Stegelmann, Frank, additional, Köhne, C, additional, Lindemann, Hans-Walter, additional, Waller, C, additional, Pfreundschuh, Michael, additional, Spiekermann, Karsten, additional, Berdel, Wolfgang E, additional, Müller, L, additional, Edinger, Matthias, additional, Mayer, Jiri, additional, Beelen, Dietrich W, additional, Bentz, Martin, additional, Link, Hartmut, additional, Hertenstein, Bernd, additional, Fuchs, R, additional, Wernli, Martin, additional, Schlegel, F, additional, Schlag, Rudolph, additional, de Wit, M, additional, Trümper, Lorenz, additional, Hebarth, H, additional, Hahn, M, additional, Thomalla, Jörg, additional, Scheid, Christof, additional, Schafhausen, Philippe, additional, Verbeek, Walter, additional, Eckart, Michael J., additional, Gassmann, Winfried, additional, Pezzutto, Antonio, additional, Schenk, Michael, additional, Brossart, Peter, additional, Geer, Thomas, additional, Bildat, Stephan, additional, Schäfer, E, additional, Hochhaus, Andreas, additional, and Hasford, Joerg, additional

Published
2017
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19. HER2/neu DNA vaccination by intradermal gene delivery in a mouse tumor model

Author

Nguyen-Hoai, Tam, Kobelt, Dennis, Hohn, Oliver, Vu, Minh D., Schlag, Peter M., Dörken, Bernd, Norley, Steven, Lipp, Martin, Walther, Wolfgang, Pezzutto, Antonio, and Westermann, Jörg

Subjects
CTL response, gene gun, DNA vaccination, human activities, complex mixtures, HER2/neu, jet injector, Research Paper
Abstract

DNA vaccines are potential tools for the induction of immune responses against both infectious disease and cancer. The dermal application of DNA vaccines is of particular interest since the epidermal and dermal layers of the skin are characterized by an abundance of antigen-presenting cells (APCs). The aim of our study was to compare tumor protection as obtained by two different methods of intradermal DNA delivery (gene gun and jet injector) in a well-established HER2/neu mouse tumor model. BALB/c mice were immunized twice with a HER2/neu-coding plasmid by gene gun or jet injector. Mice were then subcutaneously challenged with HER2/neu(+) syngeneic D2F2/E2 tumor cells. Protection against subsequent challenges with tumor cells as well as humoral and T-cell immune responses induced by the vaccine were monitored. Gene gun immunization was far superior to jet injector both in terms of tumor protection and induction of HER2/neu-specific immune responses. After gene gun immunization, 60% of the mice remained tumor-free until day 140 as compared with 25% after jet injector immunization. Furthermore, gene gun vaccination was able to induce both a strong T(H)1-polarized T-cell response with detectable cytotoxic T-lymphocyte (CTL) activity and a humoral immune response against HER2/neu, whereas the jet injector was not. Although the disadvantages that were associated with the use of the jet injector in our model may be overcome with methodological modifications and/or in larger animals, which exhibit a thicker skin and/or subcutaneous muscle tissue, we conclude that gene gun delivery constitutes the method of choice for intradermal DNA delivery in preclinical mouse models and possibly also for the clinical development of DNA-based vaccines.

Published
2012

20. DNMT3A Mutations in AML Patients: Prognostic Impact and Comparative Analysis of Mutations Burden in Diagnostic Samples, after Standard Therapy, and after Allogeneic Stem Cell Transplantation

Author

Blau, Olga, primary, Behrenbeck, Franziska, additional, Suckert, Nikola, additional, Fransecky, Lars R., additional, Baldus, Claudia D., additional, Arnold, Renate, additional, Pezzutto, Antonio, additional, Dörken, Bernd, additional, and Blau, Igor Wolfgang, additional

Published
2016
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21. 90Yttrium-Ibritumomab Tiuxetan as First Line Treatment for Follicular Non-Hodgkin Lymphoma. 5 Year Results from an International Multicenter Phase II Clinical Trial

Author

Lerch, Kristina, primary, Leng, Corinna, additional, Pinto, Antonello, additional, Linkesch, Werner, additional, Sill, Heinz, additional, Linden, Ola, additional, Viardot, Andreas, additional, Keller, Ulrich, additional, Hess, Georg, additional, Lastoria, Secondo, additional, Frigeri, Ferdinando, additional, Neik, Nicole, additional, Pott, Christiane, additional, Scholz, Christian W., additional, and Pezzutto, Antonio, additional

Published
2016
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22. Targeted transduction of T cell subsets for immunotherapy of cancer and infectious disease

Author

Uckert, Wolfgang, Pezzutto, Antonio, Buchholz, Christian, Edes, Inan, Uckert, Wolfgang, Pezzutto, Antonio, Buchholz, Christian, and Edes, Inan

Abstract

Das Ziel der vorliegenden Arbeit bestand darin, ein Vektorsystem zu entwickeln, dass den simultanen Transfer verschiedener Transgene in CD8+ und CD4+ T-Zellen und dadurch die Herstellung eines immunotherapeutischen T-Zell-Produkts ermöglicht, welches aus zwei unterschiedlich modifizierten T-Zell-Subtypen besteht. Im ersten Teil der Arbeit wurde die Targeting-Technologie von lentiviralen auf γ-retrovirale Vektoren übertragen. Anschließend wird die Herstellung von Vektoren beschrieben, die spezifisch für murines CD4 oder CD8 sind. Deren Spezifität wurde zum einen durch die exklusive Expression von GFP in CD4+ oder CD8+ Zellen und zum anderen durch den Dosis-abhängigen Verlust des GFP-Signals nach Inkubation dieser Zellen mit CD4- und CD8-blockierenden Antikörpern nachgewiesen. Im dritten Teil der Arbeit wird gezeigt, dass MVm8 und MVm4 primäre T-Zellen spezifisch transduzieren. MVm8-vermittelter Transfer des Ovalbumin (OVA)-reaktiven TZRs OT-I führte zu T-Zellen, die OVA+ Tumor-Zelllinien erkannten und Interferon-γ sezernierten. Der vierte Teil dieser Arbeit beschäftigt sich mit der in vivo Transduktion primärer T-Zellen mithilfe von MVm8, welches den OT-I-TZR und eine Luciferase transferiert (MVm8/OT-I-luc). Durch systemische Applikation von MVm8/OT-I-luc wurden T-Zellen in vivo transduziert. Durch Immunisierungen konnten antigen-spezifisches Homing, Expansion und eine anschließende Kontraktion in vivo transduzierter T-Zellen gezeigt werden. Mäuse mit starker OT-I-luc-Expression waren gegenüber einer Infektion durch OVA-transgene listeria monocytogenes geschützt. Zusammenfassend lässt sich sagen, dass das in dieser Arbeit entwickelte Vektorsystem in der Lage ist zwischen Subtypen von T-Zellen zu unterscheiden und sie simultan mit unterschiedlichen Transgenen auszustatten. Für MVm8 konnte gezeigt werden, dass es T-Zellen direkt in vivo transduzieren kann., The aim of this thesis was to generate a vector system that allows the simultaneous transfer of different transgenes into CD8+ and CD4+ T cells, allowing the generation of a immunotherapeutic T cell product comprised of two differently engineered T cell subsets. The first part of the thesis describes the transfer of the measles virus (MV) envelope-based targeting technology from lentiviral (LV) to γ-retroviral (gRV) vectors. The second part reports the generation of two targeting vectors specific for murine CD4 or CD8. The exclusive specificity of MVm4 and MVm8 was proven by expression of GFP in CD4+ and CD8+ reporter cells, respectively, but not in CD4-CD8- cells after transduction, and by a dose-dependent loss of GFP signal after incubation of reporter cells with CD4 or CD8 blocking antibodies before transduction. The third part shows that MVm8 but not MVm4 transduced primary T cells. MVm8-mediated transfer of the ovalbumin (OVA)-reactive TCR OT-I resulted in T cells secreting interferon-γ (IFNγ) upon recognition of OVA+ tumor cell lines. The final part of this thesis describes the in vivo transduction of primary T cells using MVm8 transferring OT-I and a luciferase (MVm8/OT-I-luc). To this end, B6 mice deficient for Rag2 have been repopulated with either polyclonal (B6) or monoclonal T cells derived from P14-TCR transgenic mice (P14). One day later the transferred T cells were transduced in vivo by systemic application of MVm8/OT-I-luc. Upon immunization in vivo-transduced T cells homed, expanded and contracted repeatedly in an antigen-dependent manner. Finally, mice exhibiting strong luc-signals showed improved protection against infections by OVA-transgenic listeria monocytogenes (LM-OVA). In conclusion, the viral vector system developed within this thesis is able to discriminate between the two main T cell subsets and to equip them with distinct transgenes simultaneously.

Published
2016

27. Improvement of Paraneoplastic Limbic Encephalitis after Systemic Treatment with Rituximab in a Patient with B-Cell Chronic Lymphocytic Leukemia

Author

Nogai, Hendrik, Israel-Willner, Heike, Zschenderlein, Rolf, and Pezzutto, Antonio

Subjects
Article Subject, hemic and lymphatic diseases
Abstract

Limbic encephalitis is an inflammatory disease of the central nervous system characterized by diverse neurologic symptoms including mnestic disturbances, hallucinations, and seizures as well as behavioral symptoms like depression, personality changes, and acute confusional states resembling dementia. Several antibodies have been described in the pathogenesis of limbic encephalitis. It is often a paraneoplastic syndrome associated with small cell lung cancer, breast cancer, or Hodgkin’s lymphoma among others. Here, we report a patient with B-cell chronic lymphocytic leukemia (B-CLL), presenting with otherwise unexplained neurologic symptoms consistent with limbic encephalitis. Despite intensive diagnostic procedures, no causing agent could be identified. Pleocytosis consisting of T cells was detected in the cerebrospinal fluid (CSF). We initiated anti-B-cell therapy with Rituximab for B-CLL with quick and durable resolution of symptoms. We speculate that disruption of interaction between autoreactive T and malignant B cells is responsible for the therapeutic effect of Rituximab.

Published
2013
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28. MOESM1 of High Immune Response Rates and Decreased Frequencies of Regulatory T Cells in Metastatic Renal Cell Carcinoma Patients after Tumor Cell Vaccination

Author

Pohla, Heike, Buchner, Alexander, Stadlbauer, Birgit, Frankenberger, Bernhard, Stevanovic, Stefan, Walter, Steffen, Frank, Ronald, Schwachula, Tim, Olek, Sven, Kopp, Joachim, Willimsky, Gerald, Stief, Christian, Hofstetter, Alfons, Pezzutto, Antonio, Blankenstein, Thomas, Oberneder, Ralph, and Schendel, Dolores

Abstract

High Immune Response Rates and Decreased Frequencies of Regulatory T Cells in Metastatic Renal Cell Carcinoma Patients after Tumor Cell Vaccination

Published
2012
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29. A Long-Term Safety and Efficacy Study of Givinostat in Patients with Polycythemia Vera: The First 4 Years of Treatment

Author

Finazzi, Guido, Iurlo, Alessandra, Martino, Bruno, Carli, Giuseppe, Guarini, Attilio, Noble, Richard, Vannucchi, Alessandro M., von Bubnoff, Nikolas, De Muro, Marianna, Di Bartolomeo, Paolo, McMullin, Mary Frances, Martinelli, Vincenzo, Pezzutto, Antonio, Rosti, Vittorio, Specchia, Giorgina, Bettica, Paolo, Manzoni, Sara, DI Tollo, Silvia, and Rambaldi, Alessandro

Published
2017
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30. A Two-Part Study of Givinostat in Patients with Polycythemia Vera: The Maximum Tolerated Dose Selection and the Proof of Concept Final Results

Author

Rambaldi, Alessandro, Iurlo, Alessandra, Vannucchi, Alessandro M., Noble, Richard, von Bubnoff, Nikolas, Guarini, Attilio, Hellmann, Andrzej, Martino, Bruno, Pezzutto, Antonio, Carli, Giuseppe, De Muro, Marianna, Di Bartolomeo, Paolo, McMullin, Mary Frances Frances, Cambier, Nathalie, Marolleau, Jean-Pierre, Mesa, Ruben A, Tibes, Raoul, Bettica, Paolo, Manzoni, Sara, and DI Tollo, Silvia

Published
2017
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32. Multiple myeloma cells alter the senescence phenotype of bone marrow mesenchymal stromal cells under participation of the DLK1-DIO3 genomic region

Author

Berenstein, Rimma, primary, Blau, Olga, additional, Nogai, Axel, additional, Waechter, Marlies, additional, Slonova, Ekaterina, additional, Schmidt-Hieber, Martin, additional, Kunitz, Annegret, additional, Pezzutto, Antonio, additional, Doerken, Bernd, additional, and Blau, Igor Wolfgang, additional

Published
2015
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37. First Interim Efficacy and Safety Analysis of an International Phase III Randomized Trial in Newly Diagnosed Systemic Peripheral T-Cell Lymphoma Treated with Chemotherapy with or without Alemtuzumab and Consolidated by High Dose Therapy

Author

d'Amore, Francesco, Leppa, Sirpa, da Silva, Maria Comes, Relander, Thomas, Brown, Peter De Nully, Weidmann, Eckhart, Lauritzsen, Grete Fossum, Pezzutto, Antonio, Van Hoof, Achiel, van Gelder, Michel, Doorduijn, Jeanette K., Wu, Ka Lung, Kluin-Nelemans, J. C., Lugtenburg, P. J., Jankovska, Milada, Merup, Mats, Fagerli, Unn-Merete, Walewski, Jan, Hagberg, Hans, Mariz, Jose Mario, Hansen, Per Boye, Noesslinger, Thomas, Janssens, Ann, Brandefors, Lena, Demuynck, Hilde, Schaafsma, Martyn Ronald, Christiansen, Ilse, Salek, David, Jyrkkio, Sirkku, Prochazka, Vit, Zijlstra, Josee, Bohmer, L., Greil, Richard, Stevens, Wendy, Fijnheer, Rob, Kooy, Marinus van Marwijk, Grube, Matthias, Hopfinger, Georg, Van den Neste, Eric, Jantunen, Esa, Truemper, Lorenz, Wulf, Gerald, Altmann, Bettina, Ziepert, Marita, Loeffler, Markus, Toldbod, Helle, d'Amore, Francesco, Leppa, Sirpa, da Silva, Maria Comes, Relander, Thomas, Brown, Peter De Nully, Weidmann, Eckhart, Lauritzsen, Grete Fossum, Pezzutto, Antonio, Van Hoof, Achiel, van Gelder, Michel, Doorduijn, Jeanette K., Wu, Ka Lung, Kluin-Nelemans, J. C., Lugtenburg, P. J., Jankovska, Milada, Merup, Mats, Fagerli, Unn-Merete, Walewski, Jan, Hagberg, Hans, Mariz, Jose Mario, Hansen, Per Boye, Noesslinger, Thomas, Janssens, Ann, Brandefors, Lena, Demuynck, Hilde, Schaafsma, Martyn Ronald, Christiansen, Ilse, Salek, David, Jyrkkio, Sirkku, Prochazka, Vit, Zijlstra, Josee, Bohmer, L., Greil, Richard, Stevens, Wendy, Fijnheer, Rob, Kooy, Marinus van Marwijk, Grube, Matthias, Hopfinger, Georg, Van den Neste, Eric, Jantunen, Esa, Truemper, Lorenz, Wulf, Gerald, Altmann, Bettina, Ziepert, Marita, Loeffler, Markus, and Toldbod, Helle

Published
2012

38. Isolation and characterization of T cell receptor genes for immunotherapy of Epstein-Barr-virus-associated malignancies

Author

Uckert, Wolfgang, Pezzutto, Antonio, Scheibenbogen, Carmen, Nguyen, Tuan D., Uckert, Wolfgang, Pezzutto, Antonio, Scheibenbogen, Carmen, and Nguyen, Tuan D.

Abstract

Adoptiver Transfer EBV-spezifischer, polyklonaler T-Zelllinien findet Anwendung bei Prophylaxe und Therapie EBV-assoziierter Erkrankungen. Der Ansatz hat den Nachteil der aufwändigen Herstellung der T-Zelllinien, welche aufgrund der Stimulation mit EBV transformierten B-Zelllinien oft nicht die gewünschten EBV Antigene, sondern immundominante EBV Antigene erkennen. Eine Alternative zum polyklonalen T Zelltransfer stellt die Übertragung EBV-spezifischer T-Zellrezeptoren (TCRs) dar. Dadurch können subdominante EBV Antigene angegangen werden, die von Tumorzellen tatsächlich exprimiert werden. In den hier beschriebenen Arbeiten, verwendeten wir peptidbeladene dendritische Zellen (DCs), um selektiv CD4+ T-Zellen gegen ein Epitop aus dem EBV Protein EBNA2 anzureichern. Es gibt Hinweise darauf, dass DCs sich besonders zur Stimulation von T-Zellen eignen, die subdominante EBV Antigene erkennen. Die TCR Gene eines solchen CD4+ T-Zellklons, sowie zweier CD8+ Klone, wurden in Vektoren kloniert, mit denen die EBV Spezifität der Klone auf andere T-Zellen übertragen werden sollte. Wie bereits zuvor in anderen Laboren beobachtet, waren auch unsere TCR modifizierten T-Zellen zunächst nicht in der Lage, EBV infizierte Zielzellen effektiv zu attackieren. Erst durch Modifikation der Vektorstrategie (2A Peptidlinker als Ersatz für das IRES Element (internal ribosomal entry site)) sowie der TCR Gene (Codon-Optimierung) konnte eine deutlich verbesserte Expression und Funktion der modifizierten T-Zellen erreicht werden. Außerdem hing die Effektivität der modifizierten T-Zellen essentiell von der als Zielzelle verwendeten LCL ab. Die hier beschriebenen Arbeiten zeigen die erfolgreiche Übertragung von TCRs gegen EBV Antigene auf T-Zellen. Die so modifizierten T-Zellen erlangten anti-EBV Aktivität und sprechen daher für die prinzipielle Anwendbarkeit TCR-modifizierter T-Zellen zur Behandlung EBV-assoziierter Erkrankungen., Adoptive transfer of polyclonal Epstein-Barr-virus (EBV)-specific T cell lines has been used as prophylaxis and therapy in patients with EBV-associated malignancies. This approach, however, is limited by the difficult expansion of polyclonal T cells directed mainly against dominant EBV antigens presented on EBV-transformed B cell lines (LCLs). Isolating EBV-specific T cell receptors (TCRs) for transduction of T cells is an alternative strategy to confer T cell immunity against EBV antigens including subdominant EBV antigens. In this study, we have used peptide-pulsed DCs to selectively expand EBV-specific CD4+ T cell clones against an EBNA2-derived epitope. Data suggested that peptide-pulsed DCs are particularly effective in stimulating T cells specific for subdominant EBV antigens. TCR genes from one of these clones as well as from two CD8+ T cell clones were identified by RACE PCR. TCR alpha and beta chains where then cloned into retroviral vectors for transduction of T cells to equip them with anti-EBV specificity. The TCR-modified T cells where then tested for their function towards LCLs to assess the chances for the use of EBV-redirected T cells in adoptive immunotherapy of EBV-associated disease. Like in previous reports, our EBV-specific TCRs at first did not confer effective activity against LCLs. Instead, we had to apply modifications to the TCR vectors to improve expression and function of the introduced TCRs. Codon optimization as well as replacement of the IRES site by a 2A peptide linker was required to significantly increase expression and function of transduced TCRs. Also, we found that the effectiveness of TCR transduced T cells is dependent on the target cell chosen. Our data show successful transfer of functionally active EBV-specific TCRs into T cells to render them effective against LCLs, representing the basis for the development of TCR-transgenic T cells for adoptive T cell transfer in EBV-associated disease.

Published
2010

40. Radioimmunotherapy In Relapsed/Refractory Mantle Cell Lymphoma Patients: Final Results Of a European MCL Network Phase II Trial

Author

Ferrero, Simone, primary, Pastore, Alessandro, additional, Forstpointner, Roswitha, additional, Scholz, Christian W., additional, Pezzutto, Antonio, additional, Bergmann, Lothar, additional, Truemper, Lorenz, additional, Finke, Juergen, additional, Keller, Ulrich, additional, Ladetto, Marco, additional, Hiddemann, Wolfgang, additional, Weigert, Oliver, additional, Unterhalt, Michael, additional, and Dreyling, Martin, additional

Published
2013
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43. First Interim Efficacy and Safety Analysis of an International Phase III Randomized Trial in Newly Diagnosed Systemic Peripheral T-Cell Lymphoma Treated with Chemotherapy with or without Alemtuzumab and Consolidated by High Dose Therapy

Author

d'Amore, Francesco, primary, Leppä, Sirpa, additional, da Silva, Maria Gomes, additional, Relander, Thomas, additional, De Nully Brown, Peter, additional, Weidmann, Eckhart, additional, Lauritzsen, Grete Fossum, additional, Pezzutto, Antonio, additional, Van Hoof, Achiel, additional, van Gelder, Michel, additional, Doorduijn, Jeanette K, additional, Wu, Ka Lung, additional, Kluin-Nelemans, J.C., additional, Lugtenburg, P.J., additional, Jankovska, Milada, additional, Merup, Mats, additional, Fagerli, Unn-Merete, additional, Walewski, Jan, additional, Hagberg, Hans, additional, Mariz, Jose Mario, additional, Hansen, Per Boye, additional, Nösslinger, Thomas, additional, Janssens, Ann, additional, Brandefors, Lena, additional, Demuynck, Hilde, additional, Schaafsma, Martyn Ronald, additional, Christiansen, Ilse, additional, Salek, David, additional, Jyrkkiö, Sirkku, additional, Prochazka, Vit, additional, Zijlstra, Josee, additional, Böhmer, L., additional, Greil, Richard, additional, Stevens, Wendy, additional, Fijnheer, Rob, additional, van Marwijk Kooy, Marinus, additional, Grube, Matthias, additional, Hopfinger, Georg, additional, Van den Neste, Eric, additional, Jantunen, Esa, additional, Trümper, Lorenz, additional, Wulf, Gerald, additional, Altmann, Bettina, additional, Ziepert, Marita, additional, Loeffler, Markus, additional, and Toldbod, Helle, additional

Published
2012
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44. First Interim Safety Analysis of a Phase III Randomized Trial in Newly Diagnosed Systemic Peripheral T-Cell Lymphoma Treated with CHOP Chemotherapy with or without Alemtuzumab and Consolidated by Autologous Hematopoietic Stem Cell Transplant,

Author

d'Amore, Francesco, primary, da Silva, Maria Gomes, additional, Leppa, Sirpa, additional, Relander, Thomas, additional, Pezzutto, Antonio, additional, Lauritzsen, Grete F., additional, Weidmann, Eckhart, additional, Van Gelder, Michel, additional, Merup, Mats, additional, Hagberg, Hans, additional, Fagerli, Unn-Merete, additional, Brown, Peter de Nully, additional, Hansen, Per Boye, additional, Mariz, Jose Mario, additional, Jankovska, Milada, additional, Walewski, Jan, additional, Doorduijn, Jeanette, additional, Van Hoof, Achiel, additional, Christiansen, Ilse, additional, Jyrkkiö, Sirkku, additional, Kluin-Nelemans, J.C., additional, van Marwijk Kooy, Marinus, additional, Fijnheer, Rob, additional, Stevens, Wendy, additional, Zijlstra, Josee, additional, Böhmer, L., additional, Lugtenburg, P.J., additional, Grube, Matthias, additional, Prochazka, Vit, additional, Salek, David, additional, Greil, Richard, additional, Trümper, Lorenz, additional, Wulf, Gerald, additional, Altmann, Bettina, additional, Ziepert, Marita, additional, Loeffler, Markus, additional, Jantunen, Esa, additional, Hopfinger, Georg, additional, Neste, Eric Van den, additional, and Toldbod, Helle, additional

Published
2011
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46. Sufficient and Timely Autologous Stem Cell Harvest After Chemoimmunotherapy with Alemtuzumab In Combination with Bi-Weekly CHOP as First Line Treatment In Systemic Peripheral T-Cell Lymphomas (PTCL): a Feasibility Analysis From the First Randomized Trial In Systemic PTCL (ACT trial)

Author

d'Amore, Francesco, primary, da Silva, Maria Gomes, additional, Leppa, Sirpa, additional, Pezzutto, Antonio, additional, Relander, Thomas, additional, Lauritzsen, Grete Fossum, additional, Weidmann, Eckhart, additional, Van Gelder, Michel, additional, Doorduijn, Jeanette, additional, Kluin-Nelemans, J.C., additional, van Marwijk Kooy, Marinus, additional, Fijnheer, Rob, additional, de Weerdt, Okke, additional, de Nully Brown, Peter, additional, Hansen, Per Boye, additional, Merup, Mats, additional, Grube, Matthias, additional, Mariz, Jose Mario, additional, Walewski, Jan, additional, Truemper, Lorenz, additional, Wulf, Gerald, additional, Jantunen, Esa, additional, Hopfinger, Georg, additional, and Prochazka, it, additional

Published
2010
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47. 90Yttrium Ibritumomab Tiuxetan as First Line Treatment for Follicular Lymphoma. First Results from an International Phase II Clinical Trial

Author

Scholz, Christian W., primary, Pinto, Antonello, additional, Linkesch, Werner, additional, Linden, Ola, additional, Viardot, Andreas, additional, Keller, Ulrich, additional, Hess, Georg, additional, Lerch, Kristina, additional, Frigeri, Ferdinando, additional, Arcamone, Manuela, additional, Frericks, Bernd, additional, Pott, Christiane, additional, and Pezzutto, Antonio, additional

Published
2010
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48. Phase 1 Trial of Allogeneic Gene-Modified Tumor Cell Vaccine RCC-26/CD80/IL-2 in Patients with Metastatic Renal Cell Carcinoma

Author

Buchner, Alexander, primary, Pohla, Heike, additional, Willimsky, Gerald, additional, Frankenberger, Bernhard, additional, Frank, Ronald, additional, Baur-Melnyk, Andrea, additional, Siebels, Michael, additional, Stief, Christian G., additional, Hofstetter, Alfons, additional, Kopp, Joachim, additional, Pezzutto, Antonio, additional, Blankenstein, Thomas, additional, Oberneder, Ralph, additional, and Schendel, Dolores J., additional

Published
2010
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