Targeted Interleukin-2 Therapy for Spontaneous Neuroblastoma Metastases to Bone Marrow

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Abstract
Background: 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 GD 2 (GD 2 ), in combination with recombinant human interleukin 2 (rhIL-2), is under clinical investigation. We hypothesize that targeted cytokine immunotherapy with a recombinant anti-GD 2 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 GD 2 and features both experimental and spontaneous metastases to bone marrow and liver, and 2) to assess anti-GD 2 -targeted IL-2 therapy in this model. Methods: A hybrid neuroblastoma cell line was used to generate the GD 2 -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. Results: Injection of NXS2 cells resulted in disseminated bone marrow and liver metastases exhibiting stable, but heterogeneous expression of GD 2 . Treatment with fusion protein (10 μg/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). Conclusion: 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.