Cetuximab intensifies the ADCC activity of adoptive NK cells in a nude mouse colorectal cancer xenograft model

Abstract

Natural killer (NK) cells, discovered ~40 years ago, are believed to be the most effective cytotoxic lymphocytes to counteract cancer; however, adoptive NK cell therapy in vivo has encountered certain limitations, including a lack of specificity. The drug cetuximab can mediate antibody dependent cell mediated cytotoxicity (ADCC) activity through NK cells in vivo, and has been approved for the first-line treatment of epidermal growth factor receptor (EGFR)-positive metastatic colorectal cancer (CRC). However, the ADCC activity of adoptive NK cells, induced by cetuximab in a nude mouse CRC xenograft model, has not been previously reported. The aim of the present study was to explore the ADCC activity of cetuximab combined with adoptive NK cells in CRC xenograft models with various EGFR expressions. The nude mouse xenograft models were established by subcutaneously injecting LOVO or SW620 cells. The mice were then randomly divided into 6 groups: Phosphate-buffered saline, cetuximab, human immunoglobulin G (hIgG), NK cells, hIgG plus NK cells and cetuximab plus NK cells. The ADCC antitumor activity was evaluated in these CRC models. The results indicated that the cetuximab plus NK cells group showed the greatest tumor inhibition effect compared with the NK cells group in LOVO xenograft tumor models with positive EGFR expression. However, the combination of cetuximab and NK cells did not show a stronger tumor inhibitory effect against the SW620 xenograft tumor models compared with the efficiency of NK cells. In conclusion, cetuximab could intensify the ADCC antitumor activity of adoptive NK cells towards CRC with an increased EGFR expression. The combination of cetuximab and NK cells may be a potential immunotherapy for metastatic CRC patients with positive EGFR expression.

Polymorphisms within Immune Regulatory Pathways Predict Cetuximab Efficacy and Survival in Metastatic Colorectal Cancer Patients

“…Moreover, activated NK cells may use cytokines and interferon to activate tumor suppressing macrophages [ 6 ]. In CRC cell lines and murine xenograft models, cetuximab has been shown to induce immunogenic cell death, marked by increased phagocytosis by dendritic cells [ 10 ], as well as stimulating and enhancing NK cell activity [ 14 ]. The cytotoxic agents, 5-FU and irinotecan, have also been shown to improve the ADCC activity of cetuximab across different CRC cell lines, in part by increasing cell surface EGFR expression [ 15 ].…”

<p>Monoclonal antibody therapy of solid tumors: clinical limitations and novel strategies to enhance treatment efficacy</p>

“…A further contributing mechanism of action involves suppression of VEGF (a pro-angiogenic factor) production resulting in impaired angiogenesis 57. Moreover, ADCC and CDC are also believed to contribute to cetuximab efficacy in EGFR over-expressing cancers 58,59…”

Combinatorial Immunotherapies for Metastatic Colorectal Cancer

“…Interestingly, the use of allogenic NK products—sourced from healthy blood donors, umbilical cord blood or even cell lines—may have several benefits over autologous cells [ 153 , 154 ]. Moreover, preclinical efforts indicated that ACT of peripheral blood NK cells can synergize with antibody-based targeted therapy such as cetuximab via ADCC—independently of RAS / RAF mutation status [ 155 , 156 , 157 ]. Two phase I trials affirmed safety and suggested biological activity of this combination in patients with gastrointestinal cancers ( Table 2 ).…”