A phase I study of cetuximab followed by activated and expanded NK cells for refractory nasopharyngeal cancer

Background: Natural killer cells (NK) are innate immune cells that can kill oncogenically transformed cells. In nasopharyngeal cancer (NPC), epidermal growth factor receptor (EGRF) is highly expressed, and targeted therapy using cetuximab (a chimeric monoclonal based antibody against EGFR) has been used to treat NPC. In this trial, we sought to enhance cetuximab-mediated antibody dependent cellular cytotoxicity (ADCC) by administering it in combination with activated NK cells, which bind the Fc component of the antibody via their surface CD16 receptor. To this end, we applied a method that allows vigorous expansion of activated CD16+ NK cells ex vivo by stimulation with irradiated K562-mb15-41BBL cells. We hypothesized that administration of activated NK cells after cetuximab can increase its anti-NPC activity. Aim: To determine the safety and toxicity profile of sequential cetuximab therapy, followed by concurrent cetuximab with autologous NK cells in patients with refractory nasopharyngeal cancer. Methods: A phase 1, leading on phase 2 study (NCT 02507154) was conducted in patients with recurrent/metastatic nasopharyngeal cancer who had failed at least 2 lines of prior chemotherapy. These patients were scheduled to first receive cetuximab monotherapy for 6-8 weeks, and then cetuximab followed by infusion of expanded and activated autologous NK cells, with 6 doses of subcutaneous IL-2 administered over 1 week to promote NK cell persistence. The primary end point was safety of this combination therapy; secondary endpoint was objective response of measurable disease determined by the RECIST criteria. Results: Seven patients (receiving 10 cetuximab-NK infusions in total) completed the phase 1 trial. The first 3 patients received 1 × 106 NK cells/kg; the dose was escalated to 1 × 107 NK cells/kg and administered to the remaining 4 patients. NK cell expansion, performed over 10 days, produced NK cell numbers that exceeded those planned for infusion in all 7 patients; median number of NK cell recovery was 27,400% of input NK cells (n = 10). ADCC with cetuximab against the cell line SUNE2 was tested 24 hours after NK cell administration and showed median cell killing of 87% (range 56%-95%) in a 4-hour assays at an effector:target ratio of 2:1. All patients tolerated the NK infusion well; no grade 3-4 toxicities were observed. Skin rash was the commonest side effect with cetuximab monotherapy (grade 1-2), which was not aggravated after the administration of cetuximab with NK cells. With a median follow-up of 9 months, we observed 1 partial response, 2 stable diseases, and 4 progressive diseases. Persistence of the quantity and function of NK cells beyond 8 weeks following NK therapy correlated with improved response. Conclusion: Administration of cetuximab with autologous activated CD16+ NK cells at 1 × 107 NK cells/kg is well tolerated in previously heavily treated NPC patients. Grade 1-2 skin toxicity was the predominant side effect, which did not result in termination of this combination therapy. Citation Format: Chwee Ming Lim, Anthony Liou, Michelle Poon, Liang Piu Koh, Lip Kun Tan, Noriko Shimasaki, Dario Campana, Boon Cher Goh. A phase I study of cetuximab followed by activated and expanded NK cells for refractory nasopharyngeal cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B03.