Induction of Ab3 and Ab3' antibody was associated with long-term survival after anti-G(D2) antibody therapy of stage 4 neuroblastoma.
Induction of Ab3 and Ab3' antibody was associated with long-term survival after anti-G(D2) antibody therapy of stage 4 neuroblastoma.
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发表时间：
2000-07
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通讯作者：
N. Cheung;Hong-fen Guo;G. Heller;I. Cheung
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作者：
N. Cheung;Hong-fen Guo;G. Heller;I. Cheung
缓解时使用抗 G(D2) 单克隆抗体 3F8 (Ab1) 治疗可能会延长 4 期神经母细胞瘤儿童的生存期。短暂的人抗小鼠抗体（HAMA）反应与显着更长的存活期相关（Cheung等人，J.Clin.Oncol.，16：3053-3060，1998）。因为这种反应主要是抗独特型 (Ab2)，我们推测随后诱导的独特型网络（包括抗抗独特型 (Ab3) 和抗 G(D2) (Ab3') 抗体滴度升高）可能是肿瘤控制的原因。 34 名在 > 1 岁时诊断出的 4 期神经母细胞瘤患者在化疗结束时接受了 3F8 治疗。大多数患者在诊断时存在骨髓（34 例中的 31 例）或远处骨转移（34 例中的 29 例）。 13名患者在第二次或后续缓解时接受治疗，本组12名患者在骨髓移植后有进展/持续疾病史； 21名患者在N6化疗后首次缓解时接受治疗。通过 ELISA 测量抗体治疗前、6 个月和 14 个月时的血清 HAMA、Ab3 和 Ab3' 滴度。在这 34 名患者中，14 名患者存活，13 名患者（诊断时 1.8-7.4 年）没有进展（从 3F8 治疗开始后 53-143 个月），无需进一步全身治疗。长期无进展生存期 (PFS) 和生存期与 6 个月时的 Ab3'（抗 G(D2)）反应以及 6 个月和 14 个月时的 Ab3 反应显着相关。通过将 Ab3 阈值定义为高于治疗前水平 1.1 至 2.6 的比率，高 Ab3 组和低 Ab3 组之间的 PFS 和生存率差异显着扩大。同样，在 6 或 14 个月时将 Ab3' 阈值提高至 3F8 前水平以上 300%，也增加了高 Ab3' 组与低 Ab3' 组之间 PFS 和生存曲线的差异。非独特型抗体反应（抗小鼠 IgG3 或抗肿瘤核 HUD 抗原）对 PFS 或生存没有明显影响。总之，尽管 4 期神经母细胞瘤具有高风险性，但通过 3F8 治疗可以实现无需清髓治疗的长期缓解。 Ab3 和 Ab3' 抗体反应与延长 PFS 和生存相关。我们假设在患者中成功诱导独特型网络可能是肿瘤长期控制的原因。
Treatment with anti-G(D2) monoclonal antibody 3F8 (Ab1) at the time of remission may prolong survival for children with stage 4 neuroblastoma. A transient human antimouse antibody (HAMA) response was associated with significantly longer survival (Cheung et al., J. Clin. Oncol., 16: 3053-3060, 1998). Because this response was primarily anti-idiotypic (Ab2), we postulate that the subsequent induction of an idiotype network that included an elevation of anti-anti-idiotypic (Ab3) and anti-G(D2) (Ab3') antibody titers may be responsible for tumor control. Thirty-four patients with stage 4 neuroblastoma diagnosed at >1 year of age were treated with 3F8 at the end of chemotherapy. Most had either bone marrow (31 of 34) or distant bony (29 of 34) metastases at diagnosis. Thirteen patients were treated at second or subsequent remission, and 12 patients in this group had a history of progressive/persistent disease after bone marrow transplantation; 21 patients were treated in the first remission after N6 chemotherapy. Their serum HAMA, Ab3, and Ab3' titers prior to, at 6, and at 14 months after antibody treatment were measured by ELISA. Among these 34 patients, 14 are alive, and 13 (1.8-7.4 years at diagnosis) are progression free (53-143 months from the initiation of 3F8 treatment) without further systemic therapy. Long-term progression-free survival (PFS) and survival correlated significantly with Ab3' (anti-G(D2)) response at 6 months and with Ab3 response at 6 and 14 months. By defining Ab3 threshold ranging from the ratio of 1.1 to 2.6 above pretreatment level, the difference in PFS and survival between the high-Ab3 and low-Ab3 groups became markedly widened. Similarly, increasing the Ab3' threshold at either 6 or 14 months to 300% above pre-3F8 levels also increased the spread between the high versus low Ab3' groups for both PFS and survival curves. Non-idiotype antibody responses (anti-mouse-IgG3 or anti-tumor nuclear HUD antigen) had no apparent impact on PFS or survival. In conclusion, despite the high-risk nature of stage 4 neuroblastoma, long-term remission without myeloablative therapy can be achieved with 3F8 treatment. Ab3 and Ab3' antibody response correlated with prolonged PFS and survival. We postulate that successful induction of an idiotype network in patients may be responsible for long-term tumor control.