OBJECTIVE
Chordoma is a rare bone
tumor derived from the notochord and is resistant to conventional
therapies such as
chemotherapy,
radiotherapy, and targeting
therapeutics. Expression of
epidermal growth factor receptor (EGFR) in a large proportion of
chordoma specimens indicates a potential target for therapeutic intervention. In this study the authors investigated the potential role of the anti-EGFR antibody
cetuximab in
immunotherapy for
chordoma. METHODS Since
cetuximab is a
monoclonal antibody of the
IgG1 isotype, it has the potential to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) employing natural killer (NK) cells as effectors. Polymorphisms in the CD16 allele expressed on NK cells have been shown to influence the degree of ADCC of
tumor cells, with the high-affinity
valine (V)/V allele being responsible for more lysis than the V/
phenylalanine (F) or FF allele. Unfortunately, however, only approximately 10% of the population expresses the VV allele on NK cells. An NK cell line, NK-92, has now been engineered to endogenously express
IL-2 and the high-affinity CD16 allele. These irradiated high-affinity (ha)NK cells were analyzed for lysis of
chordoma cells with and without
cetuximab, and the levels of lysis observed in ADCC were compared with those of NK cells from donors expressing the VV, VF, and FF alleles. RESULTS Here the authors demonstrate for the first time 1) that
cetuximab in combination with NK cells can mediate ADCC of
chordoma cells; 2) the influence of the NK CD16 polymorphism in
cetuximab-mediated ADCC for
chordoma cell lysis; 3) that engineered haNK cells-that is, cells transduced to express the CD16 V158 FcγRIIIa receptor-bind
cetuximab with similar affinity to normal NK cells expressing the high-affinity VV allele; and 4) that irradiated haNK cells induce ADCC with
cetuximab in
chordoma cells. CONCLUSIONS These studies provide rationale for the use of
cetuximab in combination with irradiated haNK cells for
therapy for
chordoma.