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Structure of the Group Group Leader Prof. Dr. med. Antonio Pezzutto Scientists Dr. med. Jörg Westermann Dr. med. Marion Subklewe Dr. rer. Nat. Tam Nguyen-Hoay Graduate and Undergraduate Students Oliver Schmetzer Gerd Baldenhofer Tuan Duc Nguyen Technical Assistants Margarete Gries Adoptive T-cell therapy for lymphomas Tuan Duc Nguyen in cooperation with Th. Blankenstein and W. Uckert Diseases such as Hodgkin, Nasopharyngeal Carcinomas, and Post-Transplant Lymphoproliferative Disorders (PTLD) are associated with Epstein-Barr Virus (EBV) infection. Both CD8 and CD4 clones have been generated against the EBV proteins LMP2, EBNA2 and EBNA3. Isolation of T-cell clones that target additional epitopes, i.e. from LMP1 and EBNA1 is in progress. The TCR of some of these clones have already been cloned in expression vectors, goal is the generation of transgenic T-cells for the therapy of EBV-associated diseases. PTLDs appear particularly suited for such an approach, since a large number of EBV proteins are expressed by the tumor cells. Moreover, the B-cell antigens CD19 and CD20 are particularly appealing targets for a transgenic T cell recognition: they are broadly expressed by most lymphatic leukemias and lymphomas, transient elimination of B cells does not result in severe immunedeficiency. Generation of TCR vectors recognizing epitopes of these antigens is being pursued in cooperation with Th. Blankenstein in a murine system with humanized TCR gene sequences. ty. Characterization of this polypeptide and evaluation of its properties as an immunomodulatory agent is ongoing. Selected Publications Schmetzer, O, Moldenhauer, G, Riesenberg, R, Pires, JR, Schlag, P, Pezzutto, A. (2005). Quality of recombinant protein determines the amount of autoreactivity detected against the tumorassociated epithelial cell adhesion molecule antigen: low frequency of antibodies against the natural protein. J Immunol. 174, 942-952. Westermann, J, Lessen, A, Schlimper, C, Baskaynak, G, Le Coutre, P, Dörken, B, Pezzutto A. (2006). Simultaneous cytokine analysis by cytometric bead array for the detection of leukaemia-reactive T-cells in patients with chronic myeloid leukaemia. Br J Haematol. 132, 32-35. Sebelin-Wulf, K, Nguyen, TD, Oertel, S, Papp-Vary, M, Trappe, RU, Schulzki, A, Pezzutto, A, Riess, H, Subklewe, M. (2007). Quantitative analysis of EBV-specific CD4/CD8 T cell numbers, absolute CD4/CD8 T cell numbers and EBV load in solid organ transplant recipients with PLTD. Transpl Immunol. 17, 203-210. Westermann, J, Nguyen-Hoai, T, Baldenhofer, G, Hopken, UE, Lipp, M, Dörken, B, Pezzutto, A. (2007). CCL19 (ELC) as an adjuvant for DNA vaccination: induction of a TH1-type T-cell response and enhancement of antitumor immunity. Cancer Gene Ther. 14, 523-532. Westermann, J, Kopp, J, van Lessen, A, Hecker, AC, Baskaynak, G, Le Coutre, P, Dohner, K, Dohner, H, Dörken, B, Pezzutto, A. (2007). Vaccination with autologous non-irradiated dendritic cells in patients with bcr/abl+ chronic myeloid leukaemia. Br J Haematol. 137, 297-306. Patent Applications EpCAM MHC-Klasse-II bindende Peptide und davon abgeleitete Mutanten als Verstärker der zellulären tumorreaktiven immunantwort (MDC 0506 EP) 134 Cancer Research
Molecular Immunology and Gene Therapy Thomas Blankenstein M ost of the current experimental cancer models do not reflect the pathophysiology of real-life cancer. Cancer usually occurs sporadically and is clonal in origin. Between tumor initiation and progression clinically unapparent pre-malignant cells may persist for years or decades in humans. More recently, mouse models of sporadic cancer have been developed. The mouse germ-line can be engineered with high precision so that defined genes can be switched on and off in the adult organism, ideally in a locally and timely controlled fashion. However, analysis of the immune response against sporadic tumors requires the knowledge of a tumor antigen. The adaptive immune response to sporadic cancer Ideally, a silent oncogene, for which the mice are not tolerant, is stochastically activated in individual cells. This offers the opportunity to analyze the adaptive immune response throughout the long process of malignant transformation and most closely resembles cancer in humans. In such a model with the highly immunogenic SV40 large T as dormant oncogene we showed, by generating a mouse model of sporadic cancer based on rare spontaneous activation of a dormant oncogene, that immunogenic tumors do not escape their recognition but induce tolerance. In this model, tumors derive from single cells and express a tumor-specific transplantation rejection antigen. Whereas vaccinated mice remain tumor-free throughout their lifetime, naive mice develop a progressively growing tumor after a usually very long lacency. We also showed that despite specific recognition by T cells, the tumors do not lose their intrinsic immunogenicity and are rejected after transplantation in T cell-competent recipients. Furthermore, in the primary host tumor-induced tolerance is associated with the expansion of non-functional T cells. More recently, we discovered that sporadic cancer is recognized by the adaptive immune system at the pre-malignant stage, concomitant with the induction of tumor antigen-specific tolerance. These results demonstrated that even highly immunogenic sporadic tumors are unable to induce functional cytotoxic T lymphocytes. Based on this model we conclude that immunosurveillance plays little or no role against sporadic cancer and that tumors must not escape immune recognition or destruction. Designer T cells by T cell receptor replacement T cell receptor (TCR) gene transfer is a convenient method to produce antigen-specific T cells for adoptive therapy. However, the expression of two TCR in T cells could impair their function or cause unwanted effects by mixed TCR heterodimers. With five different TCR and four different T cells, either mouse or human, we show that some TCR are strong – in terms of cell surface expression – and replace weak TCR on the cell surface resulting in exchange of antigen specificity. Two strong TCR are co-expressed. A mouse TCR replaces human TCR on human T cells. Even though it is still poorly understood why some TCR alpha/beta combinations are preferentially expressed on T cells, our data suggest that, in the future, designer T cells with exclusive tumor reactivity can be generated by T cell engineering. Dual T cell receptor expressing CD8 + T cells with tumor- and self- specificity can inhibit tumor growth without causing severe autoimmunity The engineering of antigen-specific T cells by expression of TCR genes is a convenient method for adoptive T cell immunotherapy. A potential problem is the TCR gene transfer into self-reactive T cells that survived tolerance mechanisms. We have developed an experimental system with T cells that express two TCRs with defined antigen-specificities, one recognizing a tumor-specific antigen (LCMV-gp 33 ), the other recognizing a self-antigen in the pancreas (OVA). By using tumor cells expressing high and low amount of antigen and mice expressing high and low level of self-antigen in the pancreas (RIP-OVA-Hi and RIP-OVA-Lo), we show that i) tumor rejection requires high amount of tumor-antigen, ii) severe autoimmunity requires high amount of selfantigen, and iii) if antigen expression on tumor cells is sufficient and low in the pancreas, successful adoptive T cell therapy can be obtained in the absence of severe autoimmunity. These results are shown with T cells from dual TCR transgenic mice or T cells that were redirected by TCR gene transfer. Our data demonstrate that the approach of adop- Cancer Research 135
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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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Page 189 and 190: Mitochondrial Dynamics Christiane A
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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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