CD19-specific CAR-T cells have been approved for adoptive cell therapy in several B cell malignancies. The success of this therapy has led to an increasing interest in exploiting CAR-T cells in other hematological and solid cancers (Roex, Pharmaceutics. 2020). Multiple myeloma (MM), a cancer of plasma cells, is to date an incurable disease. CAR-T cell therapy directed against the B cell maturation antigen (BCMA) expressed on MM cells has led to encouraging progression-free survival in advanced MM, yet relapses occur in most patients. Optimizing the design of the CAR molecule is part of ongoing research with a particular focus on the antigen-binding domain, both its format as well as the target (Gagelmann, Leukemia. 2020; Hanssens, Med. Res. Rev. 2021). We aim to design and evaluate nanobody-based CARs (nanoCARs) that target the protein CS1 (SLAMF7) on MM cells and may complement anti-BCMA CAR-T therapy. We chose nanobodies as an antigen-binding moiety because of the many advantages they offer over single chain variable fragments (scFvs), which are mostly used for CAR design (Hanssens, Med. Res. Rev. 2021). The target CS1 was chosen as it is universally expressed on plasma cells yet not on nonhematological cells, in contrast to other antigens investigated for MM therapy (Csi, Clin. Can. Res. 2008). To achieve this goal 3 VUB laboratories, HEIM, LMCT and ICMI, collaborate with the hematology department of the UZ Brussel. The ICMI laboratory, represented by Heleen Hanssens and Nick Devoogdt, has vast experience in nanobody development, bringing nanobodies into clinical trials, as diagnostic and therapeutic radiopharmaceuticals in different cancer types. The HEIM laboratory, represented by Kim De Veirman, performs translational research in MM. Together with the hematology department, represented by Rik Schots, HEIM has made several advancements for the treatment of MM patients. The LMCT, represented by Karine Breckpot, develops novel immunotherapy strategies, exemplified by bringing engineered dendritic cells into clinical trials. LMCT has the infrastructure and expertise to design and produce lentiviral vectors and has recently optimized protocols for T-cell transduction, which will be used in this project. Steps will be taken for clinical translation of the nanoCAR-T cell product upon successful completion of this project, building on the partners’ expertise in cell therapy, the FAGG-approved hematopoietic cell banking and clean room facilities available on site and the support of the consulting company QbD to streamline the production process (e.g., identify partners for GMP-production of lentiviral vectors).