Genotypes of NK cell KIR receptors, their ligands, and Fcγ receptors in the response of neuroblastoma patients to Hu14.18-IL2 immunotherapy.
Genotypes of NK cell KIR receptors, their ligands, and Fcγ receptors in the response of neuroblastoma patients to Hu14.18-IL2 immunotherapy.
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DOI：
10.1158/0008-5472.can-10-2211
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发表时间：
2010-12-01
期刊：
影响因子：
11.2
通讯作者：
Sondel PM
中科院分区：
文献类型：
--
作者：
Delgado DC;Hank JA;Kolesar J;Lorentzen D;Gan J;Seo S;Kim K;Shusterman S;Gillies SD;Reisfeld RA;Yang R;Gadbaw B;DeSantes KB;London WB;Seeger RC;Maris JM;Sondel PM
在鼠神经母细胞瘤（NBL）模型中，对免疫细胞因子（IC）治疗的应答依赖于自然杀伤（NK）细胞。此外，杀伤免疫球蛋白样受体（KIR）/KIR配体错配与NBL自体干细胞移植的结局改善相关。此外，对单克隆抗体的临床抗肿瘤应答与特异性多态性Fc γR等位基因相关。复发性/难治性NBL患者在儿童肿瘤组（COG）II期试验中接受hu14.18-IL 2 IC（与人IL 2连接的人源化抗GD 2单克隆抗体）。在本报告中，对这些患者进行KIR、HLA和FcR等位基因分型，以确定KIR受体-配体错配或特异性FcγR等位基因是否与抗肿瘤应答相关。入组的39名患者中有38名具有可用于分析的DNA;发现24名具有自体KIR/KIR -配体错配; 14名匹配。24例不匹配的患者中有7例在IC治疗后完全缓解或疾病改善。在匹配的患者中没有反应或可比的疾病改善。因此，KIR/KIR-配体错配与IC应答/改善相关（p = 0.03）。Fcγ R2 A 131-H/H基因型患者的缓解率高于其他Fcγ R2 A基因型患者（p = 0.06）。这些分析表明，IC治疗后复发性/难治性神经母细胞瘤患者的缓解或改善与自体KIR/KIR配体错配相关，与NK细胞在该临床缓解中的作用一致。
Response to immunocytokine (IC) therapy is dependent on natural killer (NK) cells in murine neuroblastoma (NBL) models. Furthermore, killer immunoglobulin-like receptor (KIR) / KIR-ligand mismatch is associated with improved outcome to autologous stem cell transplant for NBL. Additionally, clinical anti-tumor response to monoclonal antibodies has been associated with specific polymorphic-FcγR alleles. Relapsed/refractory NBL patients received the hu14.18-IL2 IC (humanized anti-GD2 monoclonal antibody linked to human IL2) in a Children’s Oncology Group (COG) Phase II trial. In this report, these patients were genotyped for KIR, HLA and FcR alleles to determine if KIR receptor-ligand mismatch or specific FcγR alleles were associated with anti-tumor response. Thirty-eight of 39 patients enrolled had DNA available for analysis; 24 were found to have autologous KIR/KIR -ligand mismatch; 14 were matched. Seven of 24 mismatched patients experienced either complete response or improvement of their disease after IC therapy. There was no response or comparable improvement of disease in patients who were matched. Thus KIR/KIR-ligand mismatch was associated with response/improvement to IC (p = 0.03). There was a trend towards patients with the FcγR2A 131-H/H genotype showing a higher response rate compared to other FcγR2A genotypes (p = 0.06). These analyses indicate that response or improvement of relapsed/refractory neuroblastoma patients after IC treatment is associated with autologous KIR/KIR-ligand mismatch, consistent with a role for NK cells in this clinical response.