J Neurosurg. 2018 May;128(5):1419-1427. doi: 10.3171/2017.1.JNS162610. Epub 2017 Jul 28.
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.
软骨肉瘤是一种源自脊索的罕见骨肿瘤，对化疗、放疗和靶向治疗等常规疗法具有耐药性。大量软骨肉瘤标本中表皮生长因子受体（EGFR）的表达表明其可能成为治疗干预的靶点。在这项研究中，作者研究了抗 EGFR 抗体西妥昔单抗在软骨肉瘤免疫治疗中的潜在作用。
由于西妥昔单抗是 IgG1 同种型的单克隆抗体，因此它具有利用自然杀伤（NK）细胞作为效应物介导抗体依赖性细胞介导的细胞毒性（ADCC）的潜力。NK 细胞上表达的 CD16 等位基因的多态性已被证明会影响肿瘤细胞的 ADCC 程度，高亲和力的缬氨酸（V）/V 等位基因比 V/苯丙氨酸（F）或 FF 等位基因导致更多的裂解。然而，不幸的是，只有大约 10%的人群在 NK 细胞上表达 VV 等位基因。现在已经构建了一种 NK 细胞系 NK-92，使其内源表达 IL-2 和高亲和力 CD16 等位基因。分析了用和不用西妥昔单抗的这些辐照高亲和力（ha）NK 细胞对软骨肉瘤细胞的裂解，并比较了 ADCC 中观察到的裂解水平与表达 VV、VF 和 FF 等位基因的供体 NK 细胞的裂解水平。
作者首次证明了：1）西妥昔单抗与 NK 细胞联合可以介导软骨肉瘤细胞的 ADCC；2）NK CD16 多态性在西妥昔单抗介导的软骨肉瘤细胞裂解的 ADCC 中的影响；3）经工程改造的 haNK 细胞-即转导表达 CD16 V158 FcγRIIIa 受体的细胞-与表达高亲和力 VV 等位基因的正常 NK 细胞结合西妥昔单抗的亲和力相似；4）辐照 haNK 细胞在软骨肉瘤细胞中诱导用西妥昔单抗进行 ADCC。
这些研究为西妥昔单抗联合辐照 haNK 细胞用于软骨肉瘤治疗提供了依据。
