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Structure of the Group Group Leader Prof. Dr. Thomas Blankenstein Scientists Dr. Jehad Charo Dr. Thomas Kammertöns Dr. Liang-Ping Li Dr. Joanna Listopad Dr. Jan Schmollinger Dr. Gerald Willimsky Graduate and Undergraduate Students Kathleen Anders Dana Briesemeister Christian Buschow Melinda Czeh Randi-Kristin Franke Ana Jukica Anna Kruschinski Cynthia Perez Karin Schmidt Christian Schön Björn Silkenstedt Technical Assistants Denise Barthel Kathrin Borgwald Angelika Gärtner Markus Hensel Sabrina Horn Stefanie Kupsch Tanja Specowiak Martin Textor Christel Westen Secretariat Karin Karamatskos Sylvia Klahn tively transferring TCR redirected T cells can be effective without severe side effects, even when high numbers of T cells with self-reactivity were transferred. Selected Publications Willimsky, G and Blankenstein, Th. (2005) Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature 437,141-146. Sommermeyer, D, Neudorfer, J, Weinhold, M, Leisegang, M, Engels, B, Noessner, E, Heemskerk, M, Charo, J, Schendel, D, Blankenstein, Th, Bernhard, H and Uckert, W. (2006). Designer T cells by T cell receptor replacement. Eur. J. Immunol. 36, 3052- 3059. Blankenstein, Th (2007). Do autochthonous tumors interfere with effector T cell responses? Sem. Cancer Biol. 17: 267-274. Weinhold, M, Sommermeyer, D, Uckert, W and Blankenstein, Th. (2007). Dual T cell receptor expressing CD8 + T cells with tumorand self- specificity can inhibit tumor growth without causing severe autoimmunity. J. Immunol., in press. Willimsky, G and Blankenstein, Th. (2007). The adaptive immune response to sporadic cancer. Immunol. Rev., in press. 136 Cancer Research
Molecular Cell Biology and Gene Therapy Wolfgang Uckert Antigen specificity of T cells is determined by their T cell receptor (TCR) and can be redirected by the transfer of TCRα/β genes. TCR gene-modified T cells can elicit effector functions against any target antigen. The adoptive transfer of TCR-redirected T cells into cancer patients has already led to first clinical success. The focus of our group lies on the adoptive transfer of TCR-redirected T cells for the therapy of cancer and viral diseases. We address questions related to: (i) generation of T cells with new antigen specificity by TCR gene transfer, (ii) safety aspects of TCR-redirected T cells with respect to the recognition of self-antigens, (iii) adoptive transfer of TCR-redirected T cells in mice as a prerequisite for the application of those cells in human diseases, and (iv) optimization of TCR transfer vectors. Redirection of T cell antigen specificity by TCR gene transfer Boris Engels, Haike Gelfort, Matthias Leisegang, Daniel Sommermeyer, Lilian Stärck in collaboration with Helga Bernhard, Antonio Pezzutto, Dolores Schendel Using RACE-PCR we have molecularly cloned genes of α/βTCRs recognizing tumor-associated antigens (HER2, NY-ESO-1, RCC 53, WT-1, Melan-A), virus-specific antigens (EBV-EBNA3a, EBV-LMP2a), and model antigens (C2, LCMVgp33, ovalbumin). Using retrovirus vectors, TCR genes were transferred into T cell lines and primary T cells of mouse and human origin, respectively. TCRα- and β-chains were expressed on the cell surface and functionality of transgenic TCRs was demonstrated by antigen recognition, cytokine secretion and tumor cell lysis. To increase the avidity of TCR-redirected T cells, we introduced different modifications into the TCR genes (codon optimization, additional disulfide bond, murinization of constant regions of human TCR chains) and demonstrated exemplary for the NY-ESO-1 TCR that antigen recognition can be considerably improved by TCR modification (Figure 1). Designer T cells by TCR replacement Daniel Sommermeyer in collaboration with Helga Bernhard, Thomas Blankenstein The expression of two TCRs in T cells (one endogenous and one transgenic) could impair their function or cause unwanted effects e.g. by the formation of mixed TCR heterodimers. Using five different TCRs and four different T cells, either mouse or human, we showed that some TCRs are strong – in terms of cell surface expression – and replace weak TCRs on the cell surface, resulting in exchange of antigen specificity. Two strong TCRs are co-expressed. A mouse TCR replaces human TCRs on human T cells. Even though it is poorly understood why some TCRα/β combinations are preferentially expressed on T cells, these data suggest that designer T cells with exclusive tumor reactivity can be generated by T cell engineering. A new safeguard eliminates TCR gene-modified auto-reactive T cells after adoptive transfer Eliesa Kieback in collaboration with Jehad Charo, Thomas Blankenstein By transfer of TCRα/β genes, antigen specificity of T cells can be redirected to target any antigen. However, this immunotherapy bears the risk of auto-reactive side-effects when the TCR recognizes antigens on self-tissue. We introduced a new safeguard that is based on a TCR intrinsic depletion mechanism to eliminate auto-reactive TCR-redirected T cells. By introducing a 10 amino acid tag of the c- myc protein into murine (OT-I, P14) and human (gp100) TCR sequences, tag-modified TCRs maintained equal properties compared to the wild-type receptor concerning antigen binding and triggering of effector function. Tag-modified TCR-redirected T cells could be depleted in vivo with a tagspecific antibody by antibody-mediated complement lysis and antibody-dependent cell-mediated cytotoxicity. More important, in vivo depletion of adoptively transferred T cells rescued mice from lethal autoimmune diabetes (Figure 2). This new safeguard allows the termination of adoptive therapy in case of severe side-effects. Optimization of retroviral TCR gene transfer Simone Reuß, Petra Biese, Matthias Leisegang TCR-redirected T cells are exclusively generated by retrovirus-mediated gene transfer. Therefore, packaging cell Cancer Research 137
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Research Report 2008 MDC Berlin-Buc
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Research Report 2008 (covers the pe
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Cell Polarity and Epithelial Morpho
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Molecular Cell Biology and Gene The
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Foreword Vorwort As this book was b
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which survey the quality of protein
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Two major grants from the Helmholtz
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Cardiovascular and Metabolic Diseas
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ing on this topic have made importa
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explain why a certain gene or seque
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Figure 2. Uptake of lipoprotein (A)
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Molecular Mechanisms in Embryonic F
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Cardiovascular Hormones Michael Bad
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Angiogenesis and Cardiovascular Pat
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Hypertension, Vascular Disease, Gen
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Structure of the Group Group Leader
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eceptors did not change. Thus, syst
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Mechanisms of Hypertensioninduced T
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Differentiation and Regeneration of
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Heart Diseases Coordinator: Ludwig
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Figure 1. 3D-model of the actomyosi
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Cell Polarity and Epithelial Morpho
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Molecular and Cell Biology of the (
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number of circulating antibodies to
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Genetics, Genomics, Bioinformatics,
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Physiology and Pathology of Ion Tra
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Technical Assistants Alexander Fast
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Cancer Research Krebsforschung Coor
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how they infiltrate surrounding tis
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(Photo: David Ausserhofer/Copyright
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degradation (ERAD) pathway. In the
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Structural and Functional Genomics
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ated with the deregulation of cell
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A B C Only functional Met keratinoc
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I) Conditional ablation of the Bmp
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Genetics of Tumor Progression and M
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Signaling Mechanisms in Embryonic S
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Academics Akademische Aktivitäten
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Charité-Universitätsmedizin Berli
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Helmholtz Fellows Helmholtz-Stipend
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(Photo: Cécile Otten, Research Gro
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2007 19. January Neujahrsempfang de
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Speaker Institute Titel of Seminar
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Overview Überblick
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erzielen, brauchen wir neue gemeins
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The Clinical Research Center (CRC)
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y such scientists in conjunction wi
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Zudem bietet das ECRC-Modell eine h
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(Photo: David Ausserhofer/ Copyrigh
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Business School” addressed challe
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Prof. Dr. Gary R. Lewin MDC Berlin-
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Dr. Thomas Müller Prof. Dr. Claus
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Type of Financing/Art der Finanzier
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Collaborative Research Centres (SFB
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Figures for technology transfer/Ken
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MDC MAX-DELBRÜCK-CENTRUM FÜR MOLE
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Buschow, Christian . . . . . . . .
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Herrmann, Ina . . . . . . . . . . .
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Mensen, Angela . . . . . . . . . .
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Schwarzer, Rolf . . . . . . . . . .
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Campus Map Campusplan Robert-Rössl
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How to find your way to the MDC Der
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