TRR 36:  Principles and Applications of Adoptive T Cell Therapy

• Subject Area: Medicine ; Biology
• Term: from 2006 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 16707101

Cancer is one of the leading health problems. Once classical therapies (chemotherapy, radiation therapy, surgery) have failed, other effective therapies are rarely available. Viral diseases and virus-associated cancers are, even though comparatively rare, also difficult to treat in immune-deficient patients. Therefore, there is a strong interest in utilising the immune system to fight cancer and infections. Recently, a few studies have paved the way for successful immunotherapy.
The adoptive transfer of virus-specific T cells reconstituted viral immunity in the majority of patients and, despite major side-effects, allogeneic T cells transferred in the course of bone marrow stem cell transplantation had strong anti-leukemia activity. However, since adoptive T cell therapy is difficult to perform and laborious, it is the least investigated form of immunotherapy, in comparison to antibody- or vaccine-based therapies.
New technologies to more easily generate antigen-specific T cells, the availability of a wide range of potential target antigens, and better knowledge of immune-regulation and tolerance mechanisms justify an in-depth analysis of adoptive T cell therapy. Therefore, this initiative concentrates on adoptive T cell therapy of viral disease and cancer. For this purpose, scientists from Berlin and Munich were selected for their expertise in the areas of basic and clinical immunology, molecular biology, virology and performance of innovative clinical trials.
This nationally unique endeavour will develop experimental systems to generate highly effective T cells against a broad array of target antigens. In parallel, the group will define the conditions that allow the best performance of the transfused T cells in terms of survival, migration and efficacy in experimental cancer models and through clinical trials in patients. The long-term goal is the availability of "off-the-shelf" reagents to construct sufficient numbers of human T cells with any desired specificity within a week for clinical use. These T cells will be transferred into patients, who are pre-conditioned to have a T cell "friendly" environment, and who are endangered with life-threatening viral diseases or suffer from diverse forms of cancer, including several solid tumors.

• DFG Programme: CRC/Transregios

Completed projects

• A01 - Selection of allo-restricted peptide-specific T cells for adoptive therapy of acute leukemia (Project Heads Frankenberger, Bernhard ;  Schendel, Ph.D., Dolores J. )
• A02 - Transgenic mice with a human T cell receptor repertoire (Project Head Blankenstein, Thomas )
• A03 - Use of peptide libraries to improve the generation of effector and helper T cells from immunosuppressed patients for adoptive T cell therapy - HCMV as a model (Project Heads Reinke, Petra ;  Volk, Hans-Dieter )
• A04 - EBV/CMV bi-specific T cells for adoptive therapy (Project Heads Hammerschmidt, Wolfgang ;  Moosmann, Andreas )
• A07 - T cell receptor gene transfer in CD4+ and CD8+ T cells for adoptive therapy of renal cell carcinomas (Project Heads Nößner, Elfriede ;  Uckert, Wolfgang )
• A08 - Identification of allorestricted T-cell receptors with specificity for tumor-associated antigens in B non-Hodgkin lymphoma using chronic lymphocytic leukemia as a model (Project Heads Krackhardt, Angela ;  Mocikat, Ralph )
• A10 - Immunological characterization of human donor-derived pathogen-specific T cells for adoptive T cell therapy (Project Heads Busch, Dirk ;  Neuenhahn, Michael )
• A11 - "Versatile memory T cells" for adoptive T Cell therapy - identification, characterisation and strategies for clinical applications (Project Heads Radbruch, Andreas ;  Thiel, Andreas )
• A12 - RNAi-based replacement of the endogenous by a therapeutic T cell receptor (Project Head Uckert, Wolfgang )
• A13 - Improved MHC multimer-based single cell analyses for the identification of TCR sequences with "optimal high avidity" for immunotherapy (Project Head Busch, Dirk )
• A14 - T cell therapy with chimeric antigen receptors (CARs) recognizing hepatitis B surface antigen (Project Head Protzer, Ulrike )
• B01 - Tumour stroma cells as a target of adoptively transferred T cells (Project Heads Kammertoens, Thomas ;  Nößner, Elfriede )
• B02 - Adoptive T cell therapy of tumors visualized by non-invasive in vivo imaging (Project Heads Blankenstein, Thomas ;  Na, Il-Kang )
• B03 - Graft versus leukaemia upon T cell transfer in patients with acute myeloid leukaemia and stem cell transplantation (Project Heads Borkhardt, Arndt ;  Busch, Dirk ;  Kolb, Hans-Jochem )
• B04 - The human c-MYC-gene-product as target antigen in a murine model of high grade B cell lymphoma (Project Heads Bornkamm, Georg Wilhelm ;  Gerbitz, Armin ;  Mautner, Josef )
• B05 - Effector and regulatory CD4 T cells in tumor surveillance (Project Heads Fillatreau, Simon ;  Romagnani, Ph.D., Chiara )
• B06 - Engineering of tumor microenvironments using GPI-anchored chemokine-mucin fusions and GPI-anchored TIMP proteins (Project Heads Endres, Stefan ;  Nelson, Peter Jon )
• B07 - Regulation of homeostatic T cell proliferation (Project Head Schüler, Thomas )
• B08 - Redirection of T-cells against Hepatitis B virus infected cells: comparison of chimeric and recombinant T cell receptors (Project Head Protzer, Ulrike )
• B09 - Adoptive T cell therapy to treat hepatocellular carcinoma (Project Heads Heikenwälder, Mathias ;  Willimsky, Gerald ;  Zeitz, Martin )
• B10 - Adoptive T cell therapy against tumours with defects in the antigen processing machinery (Project Head Seifert, Ulrike )
• B12 - Targeting the secretory pathway in T cells to enhance the cytolytic efficiency in adoptive immunotherapy (Project Heads Höpken, Uta Elisabeth ;  Rehm, Armin )
• B13 - Molecular mechanisms facilitating improved efficacy of adoptive T cell therapy in the liver (Project Head Knolle, Percy Alexander )
• MGK - Integrated Research Training Group (Project Heads Kammertoens, Thomas ;  Nößner, Elfriede ;  Uckert, Wolfgang )
• T01 - Selection of allo-restricted peptide-specific T cells for adoptive therapy of acute leukemia (Project Head Frankenberger, Bernhard )
• V01 - Central Tasks (Project Heads Blankenstein, Thomas ;  Busch, Dirk ;  Schendel, Ph.D., Dolores J. )
• Z01 - Core facility for the construction and characterization of T cell receptor gene-modified T lymphocytes (Project Heads Frankenberger, Bernhard ;  Schendel, Ph.D., Dolores J. ;  Uckert, Wolfgang )
• Z02 - Histomorphological analysis of T cells and the microenvironment in situ (Project Heads Loddenkemper, Christoph ;  Schulz, Stephan )
• Z03 - Platform for clinical application of TCR- and CAR-engineered T cells with defined specificity (Project Heads Hildebrandt, Martin ;  Kolb, Hans-Jochem ;  Uharek, Lutz )

• Applicant Institution: shared FU Berlin and HU Berlin through:; Charité - Universitätsmedizin Berlin
• Co-Applicant Institution: Freie Universität Berlin; Humboldt-Universität zu Berlin; Ludwig-Maximilians-Universität München; Technische Universität München (TUM)
• Participating Institution: Deutsches Rheuma-Forschungszentrum Berlin (DRFZ); Helmholtz Zentrum München; Deutsches Forschungszentrum für Gesundheit und Umwelt; Institut für Molekulare Immunologie (aufgelöst); Max-Delbrück-Centrum für Molekulare Medizin (MDC)
• Spokesperson: Professor Dr. Thomas Blankenstein