肿瘤细胞治疗研究
英文原题：KIR/KIR-ligand genotypes and clinical outcomes following chemoimmunotherapy in patients with relapsed or refractory neuroblastoma: a report from the Children's Oncology Group.
KIR/KIR-ligand genotypes and clinical outcomes following chemoimmunotherapy in patients with relapsed or refractory neuroblastoma: a report from the Children's Oncology Group.
这些发现与既往研究一致，后者显示 KIR/KIR 配体基因型与神经母细胞瘤患儿接受抗 GD2 免疫治疗后的临床结局相关。
背景：儿童肿瘤协作组ANBL1221 II期试验纳入首次复发或首次确认难治性高危神经母细胞瘤患者，给予伊立替康和替莫唑胺（I/T）联合temsirolimus（TEMS）或免疫治疗〔抗GD2抗体dinutuximab（DIN）和粒细胞-巨噬细胞集落刺激因子（GM-CSF）〕。初始队列中接受I/T/DIN/GM-CSF治疗的患者（n=17）缓解率为53%；随后又纳入患者，以进一步评估该化学免疫治疗方案。研究评估免疫相关生物标志物与临床结局（包括应答和生存）的潜在关联。方法：评估可能影响自然杀伤（NK）细胞活性的特定免疫基因型，包括杀伤细胞免疫球蛋白样受体（KIR）及其配体、Fcγ受体和NCR3。通过全血细胞计数评估白细胞总数及白细胞亚群，并采用流式细胞术分析外周血单个核细胞，以评估免疫细胞亚群及表面标志物表达与临床结局的潜在关联。采用适当的关联统计检验，并在需要时对多重比较进行Bonferroni校正。结果：在评估的免疫基因型中，某些KIR及其配体的存在或缺失与接受化学免疫治疗患者的临床结局相关，而在接受I/T/TEMS治疗者中未见这种关联。应答者与无应答者的CD161、CD56和KIR中位值存在差异，但在逻辑回归模型中未达到统计学显著性。白细胞和中性粒细胞计数与生存结局差异相关；然而，分配至化学免疫治疗组患者的事件风险增加在临床上并不显著。结论：这些发现与既往研究一致，表明在儿童神经母细胞瘤抗GD2免疫治疗后，KIR/KIR配体基因型与临床结局相关。本研究进一步证实，在临床试验中接受I/T/DIN/GM-CSF化学免疫治疗的复发或难治性患者中，KIR/KIR配体基因型具有重要意义。由于该方案目前已广泛用于首次复发或首次确认难治性疾病患者，这些结果具有重要意义。评估NK细胞及影响其功能的基因在免疫治疗应答中作用的研究仍在进行。试验注册号：NCT01767194。
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION NUMBER: NCT01767194.
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