Cancer Research - Europa

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DC-VACC Dendritic Cells as Natural Adjustments for Novel Vaccine Technologies Summary The immune system of vertebrate animals has evolved to respond to diff erent types of perturbations, such as pathogens, whilst limiting self-tissue damage. Initiation of the immune response is accomplished by unique antigen presenting cells, called dendritic cells (DC) that are resting until they encounter foreign micro-organisms or infl ammatory stimuli. Early-activated DCs trigger innate immune responses that represent the fi rst line of defence against invading pathogens to limit the infections. Subsequently, activated DCs prime antigen-specifi c immune responses, which clear the infections and give rise to immunological memory. Problem Targeting of dendritic cells for vaccination and therapeutic intervention in infectious diseases and cancer. Aim Keywords | Dendritic cells | adjuvants | pattern recognition receptors | cancer and infectious diseases | The aim of DC-VACC project is to develop novel vaccine technologies and to use DCs as a natural adjuvant with specifi city and minimum side eff ects and/or immunopathology. Early clinical trials have indicated that antigen-pulsed DCs do have great potential in the treatment of cancer. Such information will also be applicable in the eradication of infectious diseases. By defi ning novel reagents and protocols for the optimisation of DC as vaccines, this technology can then be translated to small biotechnology companies participating in this project. The basis of this proposal was to develop in situ DC targeting for use as vaccines in infectious diseases and cancer. Specifi cally, we are defi ning improved reagents and protocols for antigen delivery and targeting, which improve antigen processing and presentation by DC and can be used for vaccine technology. It will also be necessary to defi ne optimal reagents and protocols for maturation and activation of mouse and human DC in vitro for use in vaccination so that optimisation of protocols for both species is comparable – thus preparing the way for use in pre-clinical models and clinical trials in future projects. There were, thus, two specifi c objectives for the project. The specifi c objective of work package 1 was to generate tools and methods for appropriate and effi cient targeting and antigen delivery for the development of DC vaccine technology. This included the construction of viral and bacterial vectors, modifi cation of RNA, peptides and proteins, and antibody development for specifi c targeting of DC receptor repertoire. A comparison is now under progress of peptides, proteins, RNA, DNA and antigen modifi cations that allow presentation via MHC molecules. Recombinant bacterial and viral vectors are amongst the most suitable vectors for the transduction of heterologous model antigens into DC. The second objective, which is the basis of work package 2, was to defi ne optimal reagents and protocols for maturation and activation of mouse and human DC in vitro for use in vaccination so that the optimisation of protocols for both species are compared to rapidly facilitate information from pre-clinical models being transferred rapidly to clinical trials in future projects. It is fi rst necessary to identify optimal maturation stimuli of mouse and human DC by transcriptome analysis and functional assays. Thus the defi nition of such signals – including pathogen-derived products that trigger TLRs, ligands that trigger other DC receptors (such as FcR) and/or cytokines or cytokine inhibitors, and T-cellderived molecules – is critical. The aim is to obtain a clear understanding of how DCs function to induce pro-infl ammatory versus anti-infl ammatory cytokines, chemokines and their receptors, and then how they function to activate CD4+ and CD8+ T-cells. In addition, it is essential that such activation signals are also be tested for their ability to process and present antigen to T-cells, leading to a protective Th1 response. A major unique innovative feature of this project is the close interaction and exchange between groups researching in mouse and human systems, which will rapidly facilitate the translation of basic fi ndings to the clinic. Expected results The discovery and application of new adjuvants and targeting molecules, approaches for enhancing anti-tumour therapy and also in therapeutic intervention, and for vaccination in infectious diseases. Potential applications Enhancing antitumour therapy, approaches in therapeutic intervention and for vaccination in infectious diseases. Potential applications Enhancing anti-tumour therapy, approaches in therapeutic intervention and for vaccination in infectious diseases. 184 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Coordinator Anne O’Garra The Medical <strong>Research</strong> Council National Institute for Medical <strong>Research</strong> London, United Kingdom aogarra@nimr.mrc.ac.uk Partners Leonardo Biondi Biopolo Scrl – c/o IFOM Milan, Italy leonardo.biondi@biopolo.it Vincenzo Cerundolo University of Oxford Weatherall Institute of Molecular Medicine John Radcliffe Hospital Oxford, United Kingdom vincenzo.cerundolo@imm.ox.ac.uk Carl Figdor University Medical Center Nijmegen Dept. of Tumour Immunology Nijmegen Center for Molecular Life Sciences Nijmegen, The Netherlands c.figdor@ncmls.kun.nl Muriel Moser Université Libre de Bruxelles Institut de Biologie et Médicine Moléculaire Gosselies, Belgium mmoser@ulb.ac.be TREATMENT Paola Ricciardi Castagnoli University of Milano-Bicocca Dept. of Biotechnology and Bioscience Milan, Italy paola.castagnoli@unimib.it Gerold Schuler University Hospital of Erlangen Dermatologische Klinik mit Poliklinik Erlangen, Germany schuler@derma.imed.uni-erlangen.de Anna Ranghetti Sekmed srl Milan, Italy anna.ranghetti@alice.it Catherine De Greef Brucells SA Brussels, Belgium catherine.de.greef@brucells.com Project number LSHB-CT-2003-503037 EC contribution € 2 000 000 Duration 36 months Starting date 01/01/2004 Instrument STREP Project website www.biopolo.it 185
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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
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e developed by eTUMOUR is likely to
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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 and 182: Keywords | Children | cancer | leuk
Page 183 and 184: Chimaeric TCR shown in context of n
Page 185: Andrea Splendiani Leaf Bioscience s
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
Page 234 and 235: 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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