As the immune system’s first responders, natural killer (NK) cells are essential for the rapid detection and elimination of cancer. Their ability to kill cancer cells without prior sensitization makes them an ideal immunotherapy candidate. NK cells induce an anti-tumor immune response known as antibody-dependent cellular cytotoxicity (ADCC) when activating receptors, such as CD16, bind to monoclonal antibodies (mAbs) on target cells. Combining adoptive NK cell infusions with mAbs is a promising strategy for treating cancer.
Daratumumab (DARA) is a mAb that binds to CD38 and has shown clinical efficacy in treating multiple myeloma, making it an attractive candidate to augment NK cell infusion. However, as circulating NK cells express high levels of CD38, DARA can cause ADCC-dependent NK fratricide, limiting the efficacy of this therapeutic combination1. A strategy combining DARA with the adoptive transfer of CD38 knockout (CD38KO) NK cells has the potential to maximize ADCC and prevent DARA-induced fratricide, enhancing NK cell persistence. To further augment their efficacy, NK cells can be engineered to express a high- affinity CD16 (CD16-158V) receptor, which has been shown to boost ADCC, resulting in improved clinical outcomes2.
Here, we demonstrate how MaxCyte® enabled multiplexed genetic engineering in NK cells. Dual-edited NK cells improved DARA treatment and strengthened anti-tumor responses in vitro and in vivo. MaxCyte electroporation provided significant benefits including high efficiency, low toxicity and clinical scalability, empowering the rapid development of a potent cancer therapeutic.