Pediatric Neuroblastoma: Combined Treatment with Monoclonal Antibody and Cytokines Preceded by Hematopoietic Stem Cell Transplantation

Abstract

The high expression of GD2 in neuroblastoma and its restricted distribution in normal tissues make anti-GD2 monoclonal antibodies suitable for immunotherapy. A chimeric human–murine anti-GD2 monoclonal antibody called ch14.18 has shown activity against neuroblastoma in preclinical studies and early-phase clinical trials. This activity was enhanced when ch14.18 was used in combination with granulocyte–macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) to augment antibody-dependent cell-mediated cytotoxicity. The feasibility of administering ch14.18 in combination with GM-CSF, IL-2, and isotretinoin during the early post autologous hematopoietic transplantation period has been shown in two sequential phase 1 Children’s Oncology Group (COG) studies. These studies paved the way for the most recent COG study (ANBL0032), a randomized, phase 3 study, that tested whether adding immunotherapy (consisting of ch14.18 with GM-CSF and IL-2) to isotretinoin therapy, as compared to the use of isotretinoin alone, improves the survival of children with high-risk neuroblastoma who are in remission after intensive multimodal therapy which included myeloablative therapy with stem-cell rescue. Immunotherapy with ch14.18, GM-CSF, and IL-2 was associated with a significantly improved outcome (20% higher event-free survival) as compared with standard therapy in patients with high-risk neuroblastoma who achieved minimal residual disease status after intensive multimodal therapy. The standard of care for high-risk neuroblastoma has changed and now includes immunotherapy.