A Novel off-the-Shelf Trastuzumab-Armed NK Cell Therapy (ACE1702) Using Antibody-Cell-Conjugation Technology

SIMPLE SUMMARY: Chimeric antigen receptor T cell therapy has shown its potency against hematologic malignancies in autologous settings but also limited success against solid tumors with severe adverse events, including fatal cases of cytokine releasing syndrome. The aim of this research is to develop a novel off-the-shelf natural killer cell therapy against HER2-expressing cancers using Antibody-Cell Conjugation (ACC) technology and the endogenous CD16-expressing oNK cell line. ACE1702, trastuzumab-armed oNK cells with γ irradiation and cryopreservation, present superior in vitro and in vivo potency against HER2-expressing cancer cells and shows no tumorigenic potential, indicating the clinical application fighting HER2-expressing solid tumors. These findings suggest that ACC technology can be applied to allogeneic immune cells to provide off-the-shelf therapies for cancer patients. ABSTRACT: Natural killer (NK) cells harbor efficient cytotoxicity against tumor cells without causing life-threatening cytokine release syndrome (CRS) or graft-versus-host disease (GvHD). When compared to chimeric antigen receptor (CAR) technology, Antibody-Cell Conjugation (ACC) technology has been developed to provide an efficient platform to arm immune cells with cancer-targeting antibodies to recognize and attack cancer cells. Recently, we established an endogenous CD16-expressing oNK cell line (oNK) with a favorable expression pattern of NK activation/inhibitory receptors. In this study, we applied ACC platform to conjugate oNK with trastuzumab and an anti-human epidermal growth factor receptor 2 (HER2) antibody. Trastuzumab-conjugated oNK, ACE-oNK-HER2, executed in vitro and in vivo cytotoxicity against HER2-expressing cancer cells and secretion of IFNγ. The irradiated and cryopreserved ACE-oNK-HER2, designated as ACE1702, retained superior HER2-specific in vitro and in vivo potency with no tumorigenic potential. In conclusion, this study provides the evidence to support the potential clinical application of ACE1702 as a novel off-the-shelf NK cell therapy against HER2-expressing solid tumors.