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CD38-targeting antibodies such as Daratumumab and Isatuximab show good efficacy in patients with multiple myeloma. In this treatment, NK cell-mediated antibody-dependent cytotoxicity targets malignant plasma cells which express high levels of CD38. However, since NK cells also up-regulate CD38 upon activattion, these cells are depleted during the treatment, thereby limiting the clinical efficacy and increasing the risk for infectious complications. Adoptive cellular transfer of genetically modified NK cells bearing an antibody-resistant version of CD38 could be used in combination therapy with the CD38-targeting antibodies Daratumumab or Isatuximab. This project focuses on the generation and functional evaluation of NK cells with a modified CD38.We replace of the native CD38 during the ex vivo NK cell expansion process with a modified CD38 which differs only in one amino acid, effectively shielding the NK cells from antibody recognition.We expect that these CD38-modified NK cells will persist longer in the patient, thereby prolonging the effect of anti-tumor activities of infused NK cells and increasing the efficacy of anti-CD38 treatment. This project extends beyond discovery as it entails optimization of genetic modification and critical steps of GMP process development to enable a future clinical phase I trial. We aim to develop these cells into a clinical cell product for combination therapy with CD38-targeting antibodies to treat patients with multiple myeloma.