Objective Killing of cancer cells with an oncolytic adenovirus is an immunogenic phenomenon and can therefore be utilized for breaking the immunological tolerance of a tumor.Two complementary strategies can be used to enhance the T cell response towards the tumor: A) recruiting Dendritic Cells (DCs) to the tumor site to augment peptide loading onto MHC I; B) specific activation of DCs at the tumor site to increase their expression of co-stimulatory molecules for enhancement of cross-priming and T cell activation rather than cross-tolerance.As our first aim, we propose to generate three different capsid-modified oncolytic vectors expressing granulocyte-macrophage colony-stimulating factor (GM-CSF). The transgene will be driven by a replication-coupled adenoviral promoter to ensure GM-CSF production exclusively in tumor cells (an oncolytic virus replicates only in tumor cells). GM-CSF is a potent cytokine that enhances the function of antigen presenting cells (APCs) by the maturation, activation, and recruitment of DCs, macrophages and monocytes.All biologic responses crucial for DC functioning are influenced by signaling through the Toll-like receptors (TLRs), and TLR9 in particular is a key bridge between the innate and adaptive response. We propose, as our second aim, to generate an oncolytic vector containing CpG-stimulating sequences in its genome to combine oncolytic cell killing with effective delivery of CpG DNA to the endosome, where TLR9 is located.Finally, we will combine the two strategies described in aims 1 and 2, generating oncolytic vectors that are able to secrete GM-CSF for recruiting APCs to the tumor and at the same time to stimulate TLR9 in these cells. Overall we propose to capitalize on the entry biology of adenovirus for stimulation of TLR9 coupled with tumor specific secretion of immunomodulatory molecules to orchestrate immune rejection of the tumor. Fields of science natural sciencesbiological sciencesmicrobiologyvirologynatural sciencesbiological sciencesbiochemistrybiomoleculesmedical and health sciencesbasic medicineimmunologymedical and health sciencesclinical medicineoncologynatural sciencesbiological sciencesgeneticsgenomes Keywords Cancer Therapy GM-CSF Gene Therapy Health sciences Oncolytic adenovirus TLR9 Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) PEOPLE-2007-4-3.IRG - Marie Curie Action: "International Reintegration Grants" Call for proposal FP7-PEOPLE-IRG-2008 See other projects for this call Funding Scheme MC-IRG - International Re-integration Grants (IRG) Coordinator HELSINGIN YLIOPISTO EU contribution € 100 000,00 Address YLIOPISTONKATU 3 00014 Helsingin Yliopisto Finland See on map Region Manner-Suomi Helsinki-Uusimaa Helsinki-Uusimaa Activity type Higher or Secondary Education Establishments Administrative Contact Katariina Vainio-Mattila (Ms.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
