Treatment of multiple myeloma MM has evolved substantially, resulting in a significantly improved outcome for MM-patients. Agents such as proteasome inhibitors and immunomodulatory drugs [IMiDs], combined with high-dose therapy and autologous stem cell transplantation [SCT] have contributed to an increased overall survival. Unfortunately, most MM-patients relapse eventually, highlighting the need for novel treatment strategies with durable responses. Long-term survival is observed in a subset of MM-patients after allogeneic SCT and is mediated by the graft-versus-tumor [GVT] effect initiated by allogeneic T cells. This GVT-response is highly indicative of the potential of immune-based strategies in MM and instigated research into strategies to stimulate autologous T cell responses1. In that context, the applicant’s research groups performed a clinical trial studying cancer vaccination in MM, showing feasibility, safety and immunogenicity [EudraCT 2013-000795-15]. Today, it is appreciated that also invariant natural killer T [iNKT] cells contribute to the rejection of MM-cells2. Moreover, there is a growing awareness that the activity of iNKT cells and T cells is hampered via inhibitory immune checkpoints [ICPs], including but not limited to PD-1/PD-L13, 4. Therefore, novel strategies tackling MM should address activation of T cells and iNKT cells, whilst preventing ICP-mediated inhibition. We recently reported on the generation of a novel vaccine, Galsomes, i.e. lipid nano-particles [NPs] containing tumor antigen mRNA and α-galactosylceramide that activate tumor antigen-specific T cells and iNKT cells, respectively5. Therefore, Galsomes have high potential as the next generation MM-vaccine, which could be combined with ICP-blocking monoclonal antibodies [mAbs] to fully capitalize on the MM-rejecting capacity of T cells and iNKT cells. This proposal entails a preclinical study with high translational potential, in which we will study Galsomes as an MM-vaccine, studying activation of MM-specific T cells and iNKT cells in an immunocompetent mouse model of MM. We will further use a nanobody [Nb] based ICP-imaging platform6 to assess the timing and location of ICP-expression, including PD-L1, LAG-3 and TIGIT, and use this information to rationally develop a combination regimen with ICP-blocking mAbs.