Alice L. Yu

BACKGROUND: Preclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when ch14.18 is combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2. We conducted a study to determine whether adding ch14.18, GM-CSF, and interleukin-2 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma. METHODS: Patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive standard therapy (six cycles of isotretinoin) or immunotherapy (six cycles of isotretinoin and five concomitant cycles of ch14.18 in combination with alternating GM-CSF and interleukin-2). Event-free survival and overall survival were compared between the immunotherapy group and the standard-therapy group, on an intention-to-treat basis. RESULTS: A total of 226 eligible patients were randomly assigned to a treatment group. In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively. With 61% of the number of expected events observed, the study met the criteria for early stopping owing to efficacy. The median duration of follow-up was 2.1 years. Immunotherapy was superior to standard therapy with regard to rates of event-free survival (66±5% vs. 46±5% at 2 years, P=0.01) and overall survival (86±4% vs. 75±5% at 2 years, P=0.02 without adjustment for interim analyses). CONCLUSIONS: Immunotherapy with ch14.18, GM-CSF, and interleukin-2 was associated with a significantly improved outcome as compared with standard therapy in patients with high-risk neuroblastoma. (Funded by the National Institutes of Health and the Food and Drug Administration; ClinicalTrials.gov number, NCT00026312.)

A murine monoclonal antibody (monoclonal antibody 126) produced against cultured human neuroblastoma cells (LAN-1) was found to be specifically directed to a disialoganglioside (GD2) antigen preferentially expressed on both cell lines and tissues derived from melanoma and neuroblastoma. In enzyme-linked immunosorbent assays, monoclonal antibody 126 failed to react with leukemic and lymphoblastoid cells as well as with a variety of carcinoma and sarcoma cell lines. Immunohistological analysis by the immunoperoxidase technique revealed strong reactivity of monoclonal antibody 126 with frozen and formaldehyde-fixed neuroblastoma and melanoma tissues. Tissues from patients with glioma or with small cell cancer of the lung showed faint staining, whereas those from individuals with sarcoma, lymphoma, and a variety of other neoplasms proved to be negative. Sera of neuroblastoma patients showed significantly elevated GD2 levels compared to normal children (p less than 0.001) and children with other tumors (p less than 0.001) as determined by a quantitative competitive enzyme-linked immunosorbent assay. Furthermore, the GD2 serum level of one neuroblastoma patient, when followed serially, was found to correlate with progression of disease, suggesting the potential usefulness of this assay for the diagnosis and monitoring of neuroblastoma.

BACKGROUND: Myeloablative chemoradiotherapy and immunomagnetically purged autologous bone marrow transplantation has been shown to improve outcome for patients with high-risk neuroblastoma. Currently, peripheral blood stem cells (PBSC) are infused after myeloablative therapy, but the effect of purging is unknown. We did a randomised study of tumour-selective PBSC purging in stem-cell transplantation for patients with high-risk neuroblastoma. METHODS: Between March 16, 2001, and Feb 24, 2006, children and young adults (<30 years) with high-risk neuroblastoma were randomly assigned at diagnosis by a web-based system (in a 1:1 ratio) to receive either non-purged or immunomagnetically purged PBSC. Randomisation was done in blocks stratified by International Neuroblastoma Staging System stage, age, MYCN status, and International Neuroblastoma Pathology classification. Patients and treating physicians were not masked to treatment assignment. All patients were treated with six cycles of induction chemotherapy, myeloablative consolidation, and radiation therapy to the primary tumour site plus meta-iodobenzylguanidine avid metastases present before myeloablative therapy, followed by oral isotretinoin. PBSC collection was done after two induction cycles. For purging, PBSC were mixed with carbonyl iron and phagocytic cells removed with samarium cobalt magnets. Remaining cells were mixed with immunomagnetic beads prepared with five monoclonal antibodies targeting neuroblastoma cell surface antigens and attached cells were removed using samarium cobalt magnets. Patients underwent autologous stem-cell transplantation with PBSC as randomly assigned after six cycles of induction therapy. The primary endpoint was event-free survival and was analysed by intention-to-treat. The trial is registered with ClinicalTrials.gov, number NCT00004188. FINDINGS: 495 patients were enrolled, of whom 486 were randomly assigned to treatment: 243 patients to receive non-purged PBSC and 243 to received purged PBSC. PBSC were collected from 229 patients from the purged group and 236 patients from the non-purged group, and 180 patients from the purged group and 192 from the non-purged group received transplant. 5-year event-free survival was 40% (95% CI 33-46) in the purged group versus 36% (30-42) in the non-purged group (p=0·77); 5-year overall survival was 50% (95% CI 43-56) in the purged group compared with 51% (44-57) in the non-purged group (p=0·81). Toxic deaths occurred in 15 patients during induction (eight in the purged group and seven in the non-purged group) and 12 during consolidation (eight in the purged group and four in the non-purged group). The most common adverse event reported was grade 3 or worse stomatitis during both induction (87 of 242 patients in the purged group and 93 of 243 patients in the non-purged group) and consolidation (131 of 177 in the purged group vs 145 of 191 in the non-purged group). Serious adverse events during induction were grade 3 or higher decreased cardiac function (four of 242 in the purged group and five of 243 in the non-purged group) and elevated creatinine (five of 242 in the purged group and six of 243 non-purged group) and during consolidation were sinusoidal obstructive syndrome (12 of 177 in the purged group and 17 of 191 in the non-purged group), acute vascular leak (11 of 177 in the purged group and nine of 191 in the non-purged group), and decreased cardiac function (one of 177 in the purged group and four of 191 in the non-purged group). INTERPRETATION: Immunomagnetic purging of PBSC for autologous stem-cell transplantation did not improve outcome, perhaps because of incomplete purging or residual tumour in patients. Non-purged PBSC are acceptable for support of myeloablative therapy of high-risk neuroblastoma.