Professional antigen-presenting cells, such as dendritic cells (DCs) and macrophages, are targets for immunotherapy. Lentiviral vectors (LVs) have been successfully used to modify these cells in vivo. However, the broad tropism of the currently applied LVs raises several concerns, limiting the translation of LV vaccines to the clinic. It is proposed that targeting of LVs to DCs is of critical importance to improve the LV vaccine. Therefore, the first part of this project will focus on the use of LVs for in vivo gene delivery to DCs, introducing a new strategy to target DCs, i.e. the "Nanobody (Nb) display technology", in which several DC-specific Nbs will be evaluated for their capacity to target LVs to different DC subtypes. In the second part, we will de-target transgene expression from DCs. Both the targeting and de-targeting strategy should allow us to solve questions such as: 1. are DCs sufficient to induce immune responses, 2. which DC subtype is best suited and 3.is cross-priming important for the induction of tumour antigen-specific immune responses? In conclusion, this project aims at improving the potential of LVs as a generally applicable offthe-shelf anti-cancer immunotherapeutic.