Abstract
Simple SummaryChimeric 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.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.
Highlights
The secretion of IFNγ was significantly raised by ACE-oNK-human epidermal growth factor receptor 2 (HER2) engaging SK-OV-3 cells (Figure 2F and Figure S2). These results indicate that ACE-oNKHER2 is activated when encountering HER2+ cancer cells
Cancer cells with no change of basal cytotoxicity to HER2-negative cells. Both ACE-oNK-HER2 and Ctrl-oNK showed no compelling cytotoxicity to peripheral blood mononuclear cells (PBMC) from healthy donors (Figure 3B). These results demonstrate that trastuzumab conjugation by Antibody-Cell Conjugation (ACC) technology confers oNK cells with the specific cytotoxicity against HER2-expressing cancer cells
ONK cells were conjugated with trastuzumab on cell surface with >99% conjugation efficiency using ACC technology, which is more efficient than a CD16-dependent manner (Figure 1A)
Summary
Trials of T cells expressing CAR against. CD19+ lymphoma have demonstrated their efficacy [3,4], T cells expressing CARs against solid tumors have shown limited success [5,6,7]. Accumulating cases of severe adverse events in CAR-T treatment were reported, including fatal cases of cytokine releasing syndrome (CRS) [8,9,10]. Compared to CAR-T, autologous or allogeneic NK cells, including cord blood-derived NK cells and a human NK-92 cell line, possess efficient cytotoxicity against liquid and solid tumors [11,12]. Severe side effects such as cytokine release syndrome (CRS) or graft-versus-host disease (GvHD) are less likely to occur [11,12,13,14]
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