A possible mechanism of antibody-dependent cellular cytotoxicity (ADCC) of lymphokine-activated killer cells (LAK) with cetuximab for the treatment of mutated KRAS or BRAF metastatic colorectal cancer (mCRC).

Abstract

e14084 Background: Cetuximab, a chimeric IgG1 antibody, recognizing the extracellular domain of epidermal growth factor (EGFR) to inhibit the activation signaling of proliferation, angiogenesis and anti-apoptosis is used in first line mCRC treatment. In addition to this mechanism, ADCC activity has been suggested. In this study, we investigated the antitumor activity of cetuximab in combination with activated immune cells against CRC cell lines. Methods: Peripheral blood mononuclear cells (PBMCs) were activated to LAK and CD3-LAK by incubation for 4 days with IL-2 (500 U/mL) or both IL-2 and immobilized anti-CD3 antibody, respectively. LAK and CD3-LAK were co-cultured with CRC cell lines, OMUS-23 (wild-type: wt), OUMSmt (BRAFmutant: mt) and HCC-56 (KRASmt), with or without cetuximab. The antitumor activity was evaluated by adherent target detachment (ATD) assay. Results: The inductions of Fcg IIIa (CD16)+ NK cells were significantly higher in LAK than CD3-LAK (P<0.05). The ATD activity of LAK was significantly higher (P<0.05) than that of CD3-LAK. Moreover, the ATD activities of LAK in combination with cetuximab were strongly enhanced especially against mutated KRAS or BRAF tumor cells. Conclusions: Our results suggest that cetuximab in combination with Fcg IIIa+ NK lich effecter cells induced by the addition of IL-2 exerts effective anti-tumor activity. Cetuximab may therapeutic not only mCRC patients with wild-type KRAS and BRAF but also patients with mutant KRAS or BRAF by its ADCC activity.