在儿童肿瘤协作组（Children's Oncology Group）进行的ANBL1221第二阶段试验中，针对首次复发/难治性高风险神经母细胞瘤患者，联合伊立替康和替莫唑胺（I/T）和铁杉酯酶抑制剂（TEMS）或免疫治疗（抗GD2抗体地奴珠单抗（DIN）和粒细胞巨噬细胞集落刺激因子（GM-CSF））进行治疗。在最初的队列（n=17）中用I/T/DIN/GM-CSF治疗的患者中，响应率为53%。随后增加了更多的患者，以进一步评估该化疗免疫疗法方案与可能存在的免疫生物标志物之间的关系，包括治疗反应和生存率。对患者进行了特定的免疫遗传型评估，这些遗传型可以影响自然杀伤细胞（NK）的活性，包括杀手免疫球蛋白样受体（KIRs）及其配体、Fc-γ受体和NCR3。通过全血细胞计数评估了总白细胞和白细胞亚群，通过外周血单个核细胞的流式细胞术评估了免疫细胞亚群和表面标记的表达与临床结果之间的可能关联。进行了适当的统计分析。在必要时进行了Bonferroni校正。 在评估的免疫遗传型中，某些KIR及其配体的存在或不存在与化疗免疫疗法的临床结果相关，而不是与I/T/TEMS的治疗结果相关。虽然响应者和非响应者的CD161、CD56和KIR中位数值不同，但在逻辑回归模型中没有统计学意义。白细胞和中性粒细胞计数与生存结果的差异相关，但在接受化疗免疫疗法的患者中，事件风险的增加并不具有临床意义。 这些发现与早期的研究一致，显示KIR/KIR配体基因型与神经母细胞瘤儿童接受抗GD2免疫疗法后的临床结果相关。当前研究证实了在临床试验中针对复发或难治疾病患者实施的I/T/DIN/GM-CSF化疗免疫疗法中，KIR/KIR配体基因型的重要性。这些结果很重要，因为该方案现在广泛用于首次复发/难治疾病患者的治疗。评估NK细胞及其影响其功能反应的基因在免疫治疗中的作用的努力正在进行中。 NCT01767194。©作者（或其雇主）2023。根据CC BY-NC许可进行再利用。不允许商业再利用。由BMJ出版。

In the Children's Oncology Group ANBL1221 phase 2 trial for patients with first relapse/first declaration of refractory high-risk neuroblastoma, irinotecan and temozolomide (I/T) combined with either temsirolimus (TEMS) or immunotherapy (the anti-GD2 antibody dinutuximab (DIN) and granulocyte macrophage colony stimulating factory (GM-CSF)) was administered. The response rate among patients treated with I/T/DIN/GM-CSF in the initial cohort (n=17) was 53%; additional patients were enrolled to permit further evaluation of this chemoimmunotherapy regimen. Potential associations between immune-related biomarkers and clinical outcomes including response and survival were evaluated.Patients were evaluated for specific immunogenotypes that influence natural killer (NK) cell activity, including killer immunoglobulin-like receptors (KIRs) and their ligands, Fc gamma receptors, and NCR3. Total white cells and leucocyte subsets were assessed via complete blood counts, and flow cytometry of peripheral blood mononuclear cells was performed to assess the potential association between immune cell subpopulations and surface marker expression and clinical outcomes. Appropriate statistical tests of association were performed. The Bonferroni correction for multiple comparisons was performed where indicated.Of the immunogenotypes assessed, the presence or absence of certain KIR and their ligands was associated with clinical outcomes in patients treated with chemoimmunotherapy rather than I/T/TEMS. While median values of CD161, CD56, and KIR differed in responders and non-responders, statistical significance was not maintained in logistic regression models. White cell and neutrophil counts were associated with differences in survival outcomes, however, increases in risk of event in patients assigned to chemoimmunotherapy were not clinically significant.These findings are consistent with those of prior studies showing that KIR/KIR-ligand genotypes are associated with clinical outcomes following anti-GD2 immunotherapy in children with neuroblastoma. The current study confirms the importance of KIR/KIR-ligand genotype in the context of I/T/DIN/GM-CSF chemoimmunotherapy administered to patients with relapsed or refractory disease in a clinical trial. These results are important because this regimen is now widely used for treatment of patients at time of first relapse/first declaration of refractory disease. Efforts to assess the role of NK cells and genes that influence their function in response to immunotherapy are ongoing.NCT01767194.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.