Cancer Research - Europa

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• improving and testing effi cacy and the safety of antileukaemia/lymphoma chimaeric T cells in relevant pre - clinical models in vitro and in vivo in mice; • scaling-up this technology to numbers suitable for a clinical application in children with haematopoietic malig - nancies; • based on biological material obtained from our preclinical models and from children treated with these genetically engineered T cells, dissecting the interface between the host’s tumour and immune cells and using this knowledge to understand the mechanisms of anti-tumour action, validate novel targets and diagnostic tools specifi c to children aff ected with leukaemias or lymphomas. The fi nal aim is to develop a safe and effi cient adoptive immunotherapy for children with advanced or refractory malignancies. CHILDHOPE particularly focuses on three paediatric tumours: acute B-lineage lymphoblastic leukaemia, non-Hodgkin B-lineage lymphoma and acute myeloid leukaemias. Expected results The originality of the CHILDHOPE project is to exploit the immunostimulatory properties of EBV-CTLs and retarget them to leukaemia/lymphoma cells, which themselves lack many of the costimulatory molecules needed to activate CTLs. Thus, our underlying general hypothesis is that expression of chimaeric antileukaemia/lymphoma receptors on EBV-specifi c CTLs will allow these cells to retain their known safety and functionality in vivo (ability to expand and regress in response to antigen load, to persist as memory cells, and to retain antiviral activity) in children with haematopoietic malignancies while adding safety, specifi city and eff ector function directed to the residual leukaemia cells. This strategy seems highly feasible since EBV-specifi c CTL lines have been generated and reinfused in numerous patients using robust and clinically validated methodologies developed by Brenner, one of our key scientifi c advisors in the CHILDHOPE project. Unmodifi ed CD19 molecules have been manufactured and incorporated into EBV-CTLs, and tested in vitro. Our pioneering project now proposes to extend this approach against CD33+ malignancies, which represent a signifi cant part of hard-to-treat paediatric leukaemias. Another major innovation is that we will investigate modifi cations to the chimaeric receptor molecule itself, in eff orts to augment its capacity to enhance the transduction of signals that increase cytotoxic and memory eff ector function, while maintaining a high-level of safety. The T-cell proliferation should be strictly antigen-dependent and dwindle after elimination of the antigen. Finally, the CHILDHOPE project moves the fi eld forward as it brings to clinic this therapeutic modality in a phase I setting. We are confi dent that the chosen methods of gene transfer (i.e. retroviral vs. electroporation), in conjunction with our 180 suicide gene system, will provide a safe albeit suffi ciently prolonged antileukaemia eff ect in vivo in children with relapsed/refractory leukaemia/lymphoma. We anticipate that the antileukaemia/lymphoma eff ects – and consequently the survival of the treated patients – will increase with the chimaeric T-cell doses. In parallel, the CHILDHOPE project will provide preclinical data comparing the cytotoxic potency of diff erent T-cell subsets (EBV-CTLs, Cytokine Induced Killer T cells and chimaeric g9d2 T cells) in an eff ort to identify the best immune eff ector for future clinical application. Potential applications No animal model can fully dissect the tremendous complexity of the interactions between a human tumour and its host. The CHILDHOPE project is the fi rst comprehensive attempt at administrating anti-tumour chimaeric T cells in children with haematopoietic malignancies. It represents a unique opportunity to address in vivo in a complete human environment some of the most fundamental hypothesis in the fi eld of anti-tumour immunology. Our hypothesis is that targeting CD19 or CD33 will not only kill target cells but will also contribute to the release of yet unknown tumour-associated antigens (TAAs), which in turn may generate further immune activation. This mechanism known as antigen spreading may be of particular interest in tumours known for their propensity to induce antigen-loss variants. As these new TAAs may be either leukaemia/lymphoma-associated or have a broader scope of paediatric tumours, they may provide new targets for future immunotherapeutic approaches. While the CHILDHOPE project focuses at this stage on three of the most frequent paediatric tumours (acute B-lineage lymphoblastic leukaemias, non-Hodgkin B-lineage lymphoma and acute myeloid leukaemias), our innovative technology should pave the way for the generation of T lymphocytes with an antibody-dictated specifi city toward other tumourassociated antigen for which a monoclonal antibody exists. This in turn should allow us to redirect immune eff ectors towards other malignancies, including solid tumours, for which current therapeutic strategies are limited or have failed. This includes – but is not limited to – metastatic disease where T-cell therapies have had some success due to their capacity to migrate and infi ltrate distant tumour sites. In fact, it is likely that only a combination of therapies that act at key points of tumour escape pathways may help to eradicate tumour cells and also to lessen the dose-intensity of current chemotherapy regimen, a critical element of any therapeutic approach in developing individuals or in elderly patients who have reached maximum tolerable doses of anticancer drugs when their disease reoccur. Hence, our innovative therapeutic approach may provide hope for a cure for young as well as older patients with advanced or refractory tumours. CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Chimaeric TCR shown in context of native TCR signalling complex. Single-chain variable region (scFv) is composed of heavy and light chain variable domains (VH and VL) which are connected by a short peptide linker. A fl exible spacer connects VL allowing the antigen binding region to orient in diff erent directions, improving antigen recognition. The spacer is then connected to the transmembrane and intracellular portion of CD3-z. The native TCR a and b chains are also shown alongside CD4/CD8. An unmodifi ed CD3-z chain and CD3-e and CD3-g chains are also represented. Antigen binding to the native TCR leads to phosphorylation of CD3 immunoreceptor tyrosine-based activation motif (ITAMS, red boxes) which activate ZAP70, which in turn propagates further downstream signalling. Co-stimulation (in this case via CD28) is required for full T-cell activation. Coordinator Raphaël F. Rousseau MD, PhD Institut d’Hématologie Oncologie Pédiatrique INSERM U590 Centre Léon Bérard Lyon, France raphael.rousseau@lyon.fnclcc.fr Partners Christophe Caux Centre Léon Bérard Lyon, France Persis Amrolia Great Ormond Street Children’s Hospital London, United Kingdom Ettore Biagi Università Milano Bicocca Milano, Italy TREATMENT Gustav Gaudernack The Norwegian Radium Hospital Oslo, Norway Joël Plumas Établissement Français du Sang Grenoble, France Martin Pule University College of London London, United Kingdom Claudia Rossig Universitätsklinik Münster Münster, Germany Marianne C. Naafs-Wilstra International Confederation of Childhood <strong>Cancer</strong> Parent Organisation Nieuwegein, The Netherlands Laurence Lapôtre ACIES SAS Lyon, France Project number LSHC-CT-2006-037381 EC contribution € 3 208 760 Duration 48 months Starting date 01/11/2006 Instrument STREP Project website www.childhope.eu 181
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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
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DASIM Diagnostic Applications of Sy
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Expected results Primarily, the res
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Coordinator John A. Foekens Dept. o
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124 Aim Drop-Top has two major obje
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Coordinator Gorka Ochoa Progenika B
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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 and 170: Green-fl uorescence protein- expres
Page 171 and 172: Coordinator Robert Hawkins Universi
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: Keywords | Children | cancer | leuk
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
Page 221 and 222: Keywords | Anticancer therapy | onc
Page 223 and 224: Coordinator Monika Lusky Transgene
Page 225 and 226: 6 000 women over a three-year perio
Page 227 and 228: Keywords | Solid tumours | apoptosi
Page 229 and 230: Keywords | Lymphoma | leukaemia | v
Page 231: 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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