Cancer Research - Europa

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ATTACK Adoptive engineered T-cell Targeting to Activate Cancer Killing Summary Each year in the EU millions of people are diagnosed with cancer and there are over one million deaths from the disease. Thus research into improved treatments is critical and immunotherapy research, focusing on the power of the immune system, is one important new approach to treatment. The ATTACK Project is based on the development of genetically engineered T cells to target cancer. The strategies that produce engineered T cells employ the transfer of tumour targeting receptors on the outside surface of the T cells using viral vectors to help the T cells to bypass the mechanisms of immune controls triggered by the tumour. Whilst the project addresses the scientifi c basis behind this technology it has clear clinical objectives for the future. Problem Cancer is an increasing problem within the EU, and as it is predominantly a disease of old age this will continue to increase as the population ages. Despite signifi cant progress in the fi elds of early diagnosis and standard treatments including radiotherapy and chemotherapy, the outlook for most metastatic cancers remains bleak. In view of this, novel treatment approaches are being actively investigated. Aim Keywords | Engineered T-cell | recombinant TCR | chimeric immune receptor (CIR) | safety | homing | persistence | ATTACK aims to improve engineered T-cell function and to perform pre-clinical studies which will underpin future clinical trials. With this in mind, ATTACK will also enhance the understanding of the mechanisms involved in tumour evasion of immune control. The overall objectives are broken down within six work packages (WP): • optimisation of two receptor-based strategies to endow the T-cells with tumour specifi city (WP1 and 2). The fi rst strategy is based in engineering T-cells to express recombinant T-cell receptors complex (TCRα and β) recognising MHC restricted antigens at the surface of the tumour cells (WP1). The other strategy is based on chimeric immune receptors (CIR), which are scFv or small antibody molecules linked to the TCRζ (WP2); • compare the in vivo effi cacy of the redirected T-cells in physiologically relevant animal models (WP3). This will include examining the mechanisms of action of the T-cells and improving their effi cacy; • enhance cytotoxicity, proliferation, survival, tumour homing or other features to increase anti-neoplastic activity and safety of engineered T-cells for current and future applications in T-cell therapy trials (WP4); • improve protocols for T-cell selection, expansion and transduction (WP5); • looking into safety of the improved T-cells in mouse models for future clinical trials in patients (WP6). Expected results The project started in November 2005 and so far a website has been created for the dissemination of information within a secure portal for the members of the ATTACK project and external pages for dissemination to the general public. The next fi ve years will bring diff erent sets of results established in tumour cell lines and in mouse models as well as a variety of genetic and molecular data testing performance and specifi city of the two engineered T-cell strategies. • Animal models will give important clues on the fundamental mechanisms of action of the engineered T-cells and the immune response they trigger. Mouse models will allow comparison of relative effi cacy of T-cells redirected with scFv and TCR specifi c for the same antigen. • Animal studies will also enable the testing of diff erent protocols aimed at improving the engineered T-cell killing function employing chemokines or cytokines that can be applied to the clinic later. State-of-the-art imaging technology, like the dorsal skin fold window chamber, will be used to follow migration of the engineered T-cells in vivo and in real time experiments. • The development and testing of various products from the commercial partners will defi ne unique protocols for the selection and expansion of engineered T-cells. • Finally important safety data on auto-immunity, immune response against the diff erent parts of the receptor introduced in engineered T-cells will be collected from the in vivo experiments in order to gather pre-clinical data indispensable for future clinical trials. • Read outs from these results will be in peer-review publications, popular articles and other published material such as poster presentation at international meetings. Potential applications • Early phase clinical trials. • Promote and enhance discussions with national ethical bodies to understand and facilitate gene therapy trials with further pre-clinical data arisen from the ATTACK project. 168 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Coordinator Robert Hawkins University of Manchester Manchester, United Kingdom rhawkins@picr.man.ac.uk Partners TUMOR VASCULATURE: 10X TUMOR VASCULATURE: 10X NON-TUMOR VASCULATURE: 20X NON-TUMOR VASCULATURE: 20X T cells engineered to recognise a melanoma antigen and expressing Green Fluorescent Protein. The engineered T cells accumulate in tumor vasculature but not in non-tumor vasculature after T cell transfer. Real-time images were taken immediately after T cell transfer using an intravital fl uorescence microscope. (R Debets, Erasmus MC). Zelig Eshhar Weizmann Institute of Science Rehovot, Israel Reno Debets Erasmus MC Daniel den Hoed Cancer Center Rotterdam, The Netherlands Guy Gorochov Université Pierre et Marie Curie Paris, France Ton Schumacher Netherlands Cancer Institute Amsterdam, The Netherlands TREATMENT Thomas Blankenstein Max-Delbruck-Centrum für Molekulare Medizin Berlin, Germany Hinrich Abken Klinikum der Universität zu Köln Cologne, Germany Dorothy Crawford University of Edinburgh Edinburgh, United Kingdom Naomi Taylor Centre National de la Recherche Scientifique Paris, France Janos Szollosi University of Debrecen Debrecen, Hungary Hans Stauss University College of London London, United Kingdom Alberto Mantovani Humanitas Mirasole SPA Milan, Italy John Campbell Miltenyi Biotec GmbH Bergisch Gladbach, Germany Katie Binley Oxford Biomedica PLC Oxford, United Kingdom Yoram Reiter Technion-Israel Institute of Technology Haifa, Israel Balbino Alarcon Consejo Superior de Investigaciones Cientificas Madrid, Spain Anna Mondiano Fondazione Centro San Raffaele del Monde Tabor Milan, Italy Project number LSHC-CT-2005-018914 EC contribution € 11 981 087 Duration 60 months Starting date 01/11/2005 Instrument IP Project website www.attack-cancer.org 169
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PROJECT SYNOPSES CANCER RESEARCH PR
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CANCER RESEARCH PROJECTS FUNDED UND
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TABLE OF CONTENTS FOREWORD - CANCER
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Prevention 97 EPIC 98 EUROCADET 100
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CANCER: COMBATING A COMPLEX DISEASE
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Biology Cancer is a disease ethat t
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p53 activators ASPP Partner 5 NFkap
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Keywords | Angiogenesis | vasculoge
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Keywords | Tumour-host interactions
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Keywords | Breast | metastasis | ge
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Keywords | Identifi cation of novel
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Keywords | Systems biology | modell
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Keywords | Oncology | anticancer th
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• public health research coupled
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Expected results We will construct
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Potential applications Our DNA is u
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Microscopic examination of tissue s
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Pluripotent embryonic stem cells ar
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• Decryption of the leukaemia cel
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• identifi cation of molecular ta
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A B C LT-HSC CSC The Cancer Stem Ce
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X-ray diff raction of target drug c
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using pathway-specifi c reporter ce
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Keywords | Kinases | pediatric panc
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Keywords | Lymphangiogenesis | angi
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Keywords | Breast cancer | metastas
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Keywords | Mitosis | phosphorylatio
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Keywords | Therapy | genome | telom
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Keywords | Multiple myeloma | cance
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Keywords | p53 tumour suppressor |
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Development of eff ective anti-canc
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Coordinator Patrick A. Curmi INSERM
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Drosophila as a model system for tu
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Normal cell growth and epithelial l
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effi ciently with cancer cell proli
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A high-throughput assay of transcri
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Coordinator Ewa Sikora Nencki Insti
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Expected results The SIROCCO consor
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Keywords | Epigenetics | gene regul
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Keywords | Hereditary | tricarboxyl
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Keywords | HSV-1 | hepatocellular c
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Keywords | Apoptosis | autophagy |
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Keywords | Tumour | host | signalli
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Aetiology The uncontrolled cell gro
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Coordinator Rosalind Eeles Reader i
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The parallelogram approach in CARCI
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Keywords | Melanoma | genetics | na
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Keywords | Virus | bacteria | HPV |
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Keywords | Breast | prostate | gene
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Prevention The fact that preventing
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Coordinator Elio Riboli Imperial Co
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Coordinator Jan Willem Coebergh Joh
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Coordinator Jose M a Benlloch Conse
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BAMOD Breath-Gas Analysis for Molec
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BioCare Molecular Imaging for Biolo
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These centres of excellence will in
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Expected results Optimise the benef
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114 Cell proliferation and apoptosi
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COBRED Colon and Breast cancer Diag
Page 120 and 121: DASIM Diagnostic Applications of Sy
Page 122 and 123: Expected results Primarily, the res
Page 124 and 125: Coordinator John A. Foekens Dept. o
Page 126 and 127: 124 Aim Drop-Top has two major obje
Page 128 and 129: Coordinator Gorka Ochoa Progenika B
Page 130 and 131: Expected results The E.E.T.-Pipelin
Page 132 and 133: e developed by eTUMOUR is likely to
Page 134 and 135: Coordinator Angel Porgador Ben-Guri
Page 136 and 137: • the design of a compact assembl
Page 138 and 139: Potential applications We believe t
Page 140 and 141: Tumor initiation, progression to ma
Page 142 and 143: MolDiag-Paca Novel Molecular Diagno
Page 144 and 145: NEMO Nano based capsule-Endoscopy w
Page 146 and 147: OVCAD Ovarian Cancer - Diagnosis of
Page 148 and 149: P-MARK Validation of recently devel
Page 150 and 151: POC4life Multiparametric quantum do
Page 152 and 153: PROMET Prostate cancer molecular-or
Page 154 and 155: Micrometastasis in the bone marrow.
Page 156 and 157: and pharmaco-kinetics studies. This
Page 158 and 159: Coordinator Raffaella Giavazzi Isti
Page 160 and 161: • Development of tools for diagno
Page 163 and 164: Treatment Two major problems when t
Page 165 and 166: Coordinator Lluis M. Mir UMR 8121 C
Page 167 and 168: Potential applications ANGIOSTOP ha
Page 169: Green-fl uorescence protein- expres
Page 173 and 174: Expected results The BACULOGENES pr
Page 175 and 176: descriptors of the molecules to be
Page 177 and 178: Keywords | Therapeutic vaccine | im
Page 179 and 180: Keywords | Cancer chemotherapy | dr
Page 181 and 182: Keywords | Children | cancer | leuk
Page 183 and 184: Chimaeric TCR shown in context of n
Page 185 and 186: Andrea Splendiani Leaf Bioscience s
Page 187 and 188: Coordinator Anne O’Garra The Medi
Page 189 and 190: Coordinator Jacques Bartholeyns IDM
Page 191 and 192: Structure Driven Drug Design The in
Page 193 and 194: • acquire fundamental knowledge a
Page 195 and 196: Terry Jones Victoria University of
Page 197 and 198: Potential applications The use of t
Page 199 and 200: groups and management structures. T
Page 201 and 202: T. Barbui Azienda Ospedaliera-Osped
Page 203 and 204: Keywords | Mantle cell lymphoma | t
Page 205 and 206: Keywords | Hypoxia | HIF | pericell
Page 207 and 208: Keywords | Radiation-induced compli
Page 209 and 210: Keywords | Gene therapy | adenoviru
Page 211 and 212: Keywords | Dependence receptors | a
Page 213 and 214: Keywords | Photodynamic therapy | a
Page 215 and 216: Keywords | Ovarian cancer | thymidy
Page 217 and 218: Keywords | Quality assurance | clin
Page 219 and 220: Keywords | Circadian | clocks | cel
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Keywords | Anticancer therapy | onc
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Coordinator Monika Lusky Transgene
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6 000 women over a three-year perio
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Keywords | Solid tumours | apoptosi
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Keywords | Lymphoma | leukaemia | v
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Coordinator Riccardo Dolcetti Centr
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CCPRB Cancer Control using Populati
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EPCRC The European Palliative Care
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EUROCAN+PLUS Feasibility Study for
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EUSTIR A European strategy for the
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NORMOLIFE Development of new therap
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Scientifi c Model Systems The compl
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Performance of benchmarking exercis
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• markers correlating with the im
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Indices - Keywords Indices - Partne
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● disease markers 131 ● DNA dam
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● renal 77 ● replication 219
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Bos, Nico A. 56 Boskovic, Darinka 2
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Geley, Stephan 159 Georgopoulos, Li
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Lingner, Joachim 54 Linial, Michal
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Ragno, Pia 115 Rainford, Martyn 92
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Vernos, Isabelle 22 Veronesi, Umber
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● Centre Hospitalier Universitair
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● IFOM - Fondazione Istituto FIRC
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● National University of Ireland
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● University of Bari 174 ● Univ
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HOW TO OBTAIN EU PUBLICATIONS Our p
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