Lode H N, Xiang R, Varki N M, Dolman C S, Gillies S D, Reisfeld R A
The Scripps Research Institute, Department of Immunology, La Jolla, CA 92037, USA.
J Natl Cancer Inst. 1997 Nov 5;89(21):1586-94. doi: 10.1093/jnci/89.21.1586.
Advanced (stage 4) cases of neuroblastoma, a childhood cancer of the nervous system, are associated with high relapse rates, even after intensive chemotherapy, radiotherapy, and autologous bone marrow transplantation. Therefore, the use of monoclonal antibodies directed against the neuroblastoma tumor marker disialoganglioside GD2 (GD2), in combination with recombinant human interleukin 2 (rhIL-2), is under clinical investigation. We hypothesize that targeted cytokine immunotherapy with a recombinant anti-GD2 antibody-interleukin 2 fusion protein (ch14.18-IL-2) is superior to a combination of ch14.18 and rhIL-2. Our purpose was as follows: 1) to develop a syngeneic model for murine neuroblastoma that expresses GD2 and features both experimental and spontaneous metastases to bone marrow and liver, and 2) to assess anti-GD2-targeted IL-2 therapy in this mode.
A hybrid neuroblastoma cell line was used to generate the GD2-positive NXS2 cell line. Bone marrow and liver metastases were quantified by reverse transcription-polymerase chain reaction for tyrosine hydroxylase and by organ weight or counts of macroscopic tumor foci, respectively. All P values reported are two-sided.
Injection of NXS2 cells resulted in disseminated bone marrow and liver metastases exhibiting stable, but heterogeneous expression of GD2. Treatment with fusion protein (10 microg/day for 6 days) effectively suppressed growth of both experimental and spontaneous metastases to bone marrow and liver (P<.001). In contrast, a mixture of rhIL-2 and ch14.18 at equivalent dose levels was inefficient. Only mice treated with ch14.18-IL-2 showed a twofold prolongation in life span (P<.001).
Targeted IL-2 therapy with a ch14.18-IL-2 fusion protein elicits an effective antitumor response. Our data suggest that a study of ch14.18-IL-2 as an adjuvant treatment in patients with minimal residual disease may be of value.
神经母细胞瘤是一种儿童期神经系统癌症，晚期（4期）病例即便经过强化化疗、放疗和自体骨髓移植，复发率仍很高。因此，针对神经母细胞瘤肿瘤标志物双唾液酸神经节苷脂GD2（GD2）的单克隆抗体与重组人白细胞介素2（rhIL-2）联合使用正在进行临床研究。我们假设，用重组抗GD2抗体-白细胞介素2融合蛋白（ch14.18-IL-2）进行靶向细胞因子免疫疗法优于ch14.18和rhIL-2的联合疗法。我们的目的如下：1）建立一种表达GD2的小鼠神经母细胞瘤同基因模型，该模型具有向骨髓和肝脏的实验性转移和自发性转移；2）在该模型中评估抗GD2靶向IL-2疗法。
使用一种杂交神经母细胞瘤细胞系来生成GD2阳性的NXS2细胞系。分别通过逆转录-聚合酶链反应检测酪氨酸羟化酶来定量骨髓转移，通过器官重量或宏观肿瘤灶计数来定量肝脏转移。所有报告的P值均为双侧。
注射NXS2细胞导致骨髓和肝脏出现播散性转移，GD2表达稳定但存在异质性。用融合蛋白治疗（10微克/天，共6天）有效抑制了向骨髓和肝脏的实验性转移和自发性转移的生长（P<0.001）。相比之下，同等剂量水平的rhIL-2和ch14.18混合物效果不佳。只有用ch14.18-IL-2治疗的小鼠寿命延长了两倍（P<0.001）。
用ch14.18-IL-2融合蛋白进行靶向IL-2疗法可引发有效的抗肿瘤反应。我们的数据表明，研究ch14.18-IL-2作为微小残留病患者的辅助治疗可能具有价值。
