Safety and feasibility of blockade of NK group-2 member-A receptor in natural killer cells combined with cetuximab antibody in patients with advanced gastric adenocarcinoma

Abstract

Purpose: Blocking of inhibitory receptors such as NK group-2 member-A (NKG2A) enhances tumor immunity of natural killer (NK) cells. Additionally, antibody-dependent cellular cytotoxicity (ADCC) is an important cytotoxic modality of action of NK cells, which act as a functional bridge between innate and adaptive immunity. Here, we investigated the safety and feasibility of anti-NKG2A antibody-pretreated NK cells combined with IgG1 antibody (cetuximab) in patients with advanced gastric adenocarcinoma (GAC). Method: In this pilot study, treatment was initiated with cetuximab-based chemotherapy, followed by three times adoptive administration of anti-NKG2A pretreated NK cells (at doses 7×108 cells/injection) at 5-day intervals in three unresectable and locally advanced GAC patients who enrolled regarding vital signs and clinical characteristics. The clinical signs, laboratory parameters, and CTCAE (Common Terminology Criteria for Adverse Events) were documented for a safety and feasibility assessment. Results: The expanded cells were confirmed to be enriched in NK cells with high expression of CD56 (88.1%) and low expression of NKG2A (0.22%). The combination NK cell therapy was well tolerated, with transient adverse events. All patients were alive at the last follow-up (24 weeks). All patients showed overall decreases in tumor size and CA 19–9 level 4 weeks after combination therapy. However, two patients showed progressive disease (PD) after 12 weeks and the level of CA19-9 was increased in all three patients after 24 weeks. Conclusion: In conclusion, this study demonstrated the safety and feasibility of infusing high doses of anti-NKG2A pretreated NK cells combined with cetuximab in patients with GAC.

Keywords: Stomach Neoplasms, Receptors, Natural Killer Cells, Monalizumab, Immune Checkpoint Proteins,, Cetuximab