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Abstract：
BACKGROUND: Neuroblastic tumors (NBTs) originate from a block in the process of differentiation. Histologically, NBTs are classified in neuroblastoma (NB), ganglioneuroblastoma (GNB), and ganglioneuroma (GN). Current therapy for high-risk (HR) NB includes chemotherapy, surgery, radiotherapy, and anti-GD2 monoclonal antibodies (mAbs). Anti-GD2 mAbs induce immunological cytoxicity but also direct cell death.
METHODS: We report on patients treated with naxitamab for chemorefractory NB showing lesions with long periods of stable disease. Target lesions with persisting 123I-Metaiodobenzylguanidine (MIBG) uptake after 4 cycles of immunotherapy were further evaluated by functional Magnetic Resonance Imaging (MRI) and/or Fluorodeoxyglucose (FDG)-positron emission tomography (PET). MIBG avid lesions that became non-restrictive on MRI (apparent diffusion coefficient (ADC) > 1) and/or FDG-PET negative (SUV < 2) were biopsied.
RESULTS: Twenty-seven relapse/refractory (R/R) HR-NB patients were enrolled on protocol Ymabs 201. Two (7.5%) of the 27 showed persistent bone lesions on MIBG, ADC high, and/or FDG-PET negative. Forty-four R/R HR-NB patients received chemo-immunotherapy. Twelve (27%) of the 44 developed persistent MIBG+ but FDG-PET- and/or high ADC lesions. Twelve (86%) of the 14 cases identified were successfully biopsied producing 16 evaluable samples. Histology showed ganglioneuroma maturing subtype in 6 (37.5%); ganglioneuroma mature subtype with no neuroblastic component in 4 (25%); differentiating NB with no Schwannian stroma in 5 (31%); and undifferentiated NB without Schwannian stroma in one (6%). Overall, 10 (62.5%) of the 16 specimens were histopathologically fully mature NBTs.
CONCLUSIONS: Our results disclose an undescribed mechanism of action for naxitamab and highlight the limitations of conventional imaging in the evaluation of anti-GD2 immunotherapy clinical efficacy for HR-NB.
METHODS: We report on patients treated with naxitamab for chemorefractory NB showing lesions with long periods of stable disease. Target lesions with persisting 123I-Metaiodobenzylguanidine (MIBG) uptake after 4 cycles of immunotherapy were further evaluated by functional Magnetic Resonance Imaging (MRI) and/or Fluorodeoxyglucose (FDG)-positron emission tomography (PET). MIBG avid lesions that became non-restrictive on MRI (apparent diffusion coefficient (ADC) > 1) and/or FDG-PET negative (SUV < 2) were biopsied.
RESULTS: Twenty-seven relapse/refractory (R/R) HR-NB patients were enrolled on protocol Ymabs 201. Two (7.5%) of the 27 showed persistent bone lesions on MIBG, ADC high, and/or FDG-PET negative. Forty-four R/R HR-NB patients received chemo-immunotherapy. Twelve (27%) of the 44 developed persistent MIBG+ but FDG-PET- and/or high ADC lesions. Twelve (86%) of the 14 cases identified were successfully biopsied producing 16 evaluable samples. Histology showed ganglioneuroma maturing subtype in 6 (37.5%); ganglioneuroma mature subtype with no neuroblastic component in 4 (25%); differentiating NB with no Schwannian stroma in 5 (31%); and undifferentiated NB without Schwannian stroma in one (6%). Overall, 10 (62.5%) of the 16 specimens were histopathologically fully mature NBTs.
CONCLUSIONS: Our results disclose an undescribed mechanism of action for naxitamab and highlight the limitations of conventional imaging in the evaluation of anti-GD2 immunotherapy clinical efficacy for HR-NB.
摘要：
背景：神经母细胞性肿瘤（NBTs）起源于分化过程中的阻滞。组织学上,NBTs被分类为神经母细胞瘤(NB)，神经节神经母细胞瘤（GNB），和神经节神经瘤（GN）。目前高危（HR）NB的治疗包括化疗，手术,放射治疗,和抗GD2单克隆抗体(mAb)。抗GD2单克隆抗体诱导免疫细胞毒性，但也直接导致细胞死亡。
方法：我们报告了接受纳西他单抗治疗化疗难治性NB的患者，显示疾病长期稳定的病变。通过功能磁共振成像（MRI）和/或氟脱氧葡萄糖（FDG）-正电子发射断层扫描（PET）进一步评估了4个周期的免疫治疗后持续摄取123I-甲基碘苄基胍（MIBG）的靶病变。活检在MRI上变得非限制性(表观扩散系数(ADC)>1)和/或FDG-PET阴性(SUV<2)的MIBG狂热病变。
结果：27例复发/难治性（R/R）HR-NB患者纳入方案Ymab201。27人中有2人（7.5％）在MIBG上显示出持续性骨病变，ADC高,和/或FDG-PET阴性。44例R/RHR-NB患者接受化学免疫治疗。44例患者中有12例（27%）出现持续性MIBG+但FDG-PET-和/或高ADC病变。确定的14例病例中有12例（86％）成功进行了活检，产生了16个可评估的样本。组织学显示神经节细胞瘤成熟亚型为6种（37.5％）；神经节细胞瘤成熟亚型，无神经母细胞成分4种（25％）；分化无Schwannian基质的NB为5（31％）；无Schwannian基质的未分化NB为1（6％）。总的来说,16个标本中有10个（62.5％）是组织病理学上完全成熟的NBT。
结论：我们的研究结果揭示了纳他他单抗的作用机制，并强调了常规影像学在评估抗GD2免疫治疗HR-NB临床疗效方面的局限性。
方法：我们报告了接受纳西他单抗治疗化疗难治性NB的患者，显示疾病长期稳定的病变。通过功能磁共振成像（MRI）和/或氟脱氧葡萄糖（FDG）-正电子发射断层扫描（PET）进一步评估了4个周期的免疫治疗后持续摄取123I-甲基碘苄基胍（MIBG）的靶病变。活检在MRI上变得非限制性(表观扩散系数(ADC)>1)和/或FDG-PET阴性(SUV<2)的MIBG狂热病变。
结果：27例复发/难治性（R/R）HR-NB患者纳入方案Ymab201。27人中有2人（7.5％）在MIBG上显示出持续性骨病变，ADC高,和/或FDG-PET阴性。44例R/RHR-NB患者接受化学免疫治疗。44例患者中有12例（27%）出现持续性MIBG+但FDG-PET-和/或高ADC病变。确定的14例病例中有12例（86％）成功进行了活检，产生了16个可评估的样本。组织学显示神经节细胞瘤成熟亚型为6种（37.5％）；神经节细胞瘤成熟亚型，无神经母细胞成分4种（25％）；分化无Schwannian基质的NB为5（31％）；无Schwannian基质的未分化NB为1（6％）。总的来说,16个标本中有10个（62.5％）是组织病理学上完全成熟的NBT。
结论：我们的研究结果揭示了纳他他单抗的作用机制，并强调了常规影像学在评估抗GD2免疫治疗HR-NB临床疗效方面的局限性。
