TARGETED INTERLEUKIN-2 THERAPY FOR SPONTANEOUS NEUROBLASTOMA METASTASES TO BONE-MARROW

Background: Advanced (stage 4) cases of neuroblastoma, a childhood can cer of the nervous system, are associated with high relapse rates, eve n after intensive chemotherapy, radiotherapy, and autologous bone marr ow transplantation. Therefore, the use of monoclonal antibodies direct ed 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 i mmunotherapy with a recombinant anti-GD(2) antibody-interleukin 2 fusi on 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 fo r murine neuroblastoma that expresses GD(2), and features both experim ental and spontaneous metastases to bone marrow and liver, and 2) to a ssess anti-GD(2)-targeted IL-2 therapy in this model, Methods: A hybri d neuroblastoma cell line was used to generate the GD(2)-positive NXS2 cell line, Bone marrow and liver metastases were quantified by revers e transcription-polymerase chain reaction for tyrosine hydroxylase and by organ weight or counts of macroscopic tumor foci, respectively, Al l P values reported are two-sided, Results: Injection of NXS2 cells re sulted in disseminated bone marrow and liver metastases exhibiting sta ble, but heterogeneous expression of GD(2), Treatment with fusion prot ein (10 mu g/day for 6 days) effectively suppressed growth of both exp erimental and spontaneous metastases to bone marrow and liver (P<.001) , In contrast, a mixture of rhIL-2 and ch14.18 at equivalent dose leve ls was inefficient, Only mice treated with ch14.18-IL-2 showed a twofo ld prolongation in life span (P<.001), Conclusion: Targeted IL-2 thera py with a ch14.18-IL-2 fusion protein elicits an effective antitumor r esponse, 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.