Final Activity Report Summary - NK DEFENSE AND THERAPY (Natural killer cell-mediated anti-viral and anti-tumour defence and therapy: Integrated research training in molecular medicine ...) This project combined basic and applied research in immunotechnology with a focused joint training program in state-of-the-art immunology/virology, bioinformatics as well as principles of patent rights and the biotech business in half-yearly network-wide series of lectures/courses. As natural killer (NK) cells possess pivotal roles in the defence against viral infections and cancer, we have investigated in the research part the roles of NK cells in the response to cytomegalovirus (CMV) and tumours, studying immune evasion mechanisms and developing strategies of NK cell-based immunotherapies. In one part of the project subsets of NK cells in peripheral blood, their interaction with CMV-infected cells, and characteristics of tumour-invading NK cells have been investigated. NK subsets and receptors functioning in anti-viral and anti-tumour responses have been defined. Partner 4 has studied the response of NK cells to CMV-infected dendritic cells and has defined the receptors p46 and DNAM-1 involved in recognition of CMV. Partners 3 and 2 have identified novel CMV immune evasion mechanisms targeted at the NKG2D receptor and the Fc-gammaIII receptor (CD16), supporting their roles in NK immune defences. Partner 5 has demonstrated a critical role of the NK receptor p46 in the prevention of tumour development. Partner 1 has shown that NK cells in human carcinomas have reduced expression of CD16 and increased cells with the NKG2A and NKG2C receptors, supporting their importance in tumour immunosurveillance. Partner 7 has developed a method to identify so far unrecognized ligands of receptors, which will be useful to identify target structures for NK receptors on virally infected and tumour cells. In a second part of the project techniques and tools for NK-based immunotherapies were developed. Based on the recent availability of cord blood (CB) in CB banks, CB NK cells were characterised by partner 6 and a method to produce large amounts of NK cells from CB stem cells was established by partner 1 to provide a basis for NK cell infusions in immunotherapy. Partner 2 has provided basic information for antibody-based immunotherapy of CMV infections by identifying viral proteins eliciting NK-mediated antibody-dependent cellular cytotoxicity (ADCC) responses. The central part of the immunotherapy project was the generation of bispecific reagents in a specific TandAb format by the company partner 10. To achieve this, human scFv for activating NK receptors such as CD16A, NKG2D and p46 were first isolated. Based on their capacity to induce NK killing the CD16A and NKG2D reagents were further developed, the CD16A reagent has been linked in the TandAb format with a reagent mediating binding to leukaemia antigens and will be evaluated in leukaemia therapy. In the training part of the project for the Marie Curie fellows, we have combined extensive research training in the individual laboratories with network-wide half-yearly undertaken series of lectures and courses. The half-yearly meetings, summer and winter schools, consisted of state-of-the-art lectures in the research field (workshops) and courses in bioinformatics by partner 8, the European Bioinformatics Institute, in principles of priority rights by partner 10, the European Patent Organisation, and in management of the biotech business by partner 12, the Vienna University of Economics and Business Administration. Based on the feedback from fellows and teachers involved, this format has been very successful, fulfilling the needs of students in the biotechnology field to be trained in supplementary skills useful for their later careers as researchers at universities as well as in companies. Thus we believe that this is an exemplary format, providing all with basic knowledge and expertise valuable to extend job and career opportunities from top level researcher and including a full range of additional possibilities from patent officers to founders of start-ups in the biotech business.
