Promising Therapeutic Targets in Neuroblastoma

Abstract

Neuroblastoma, the most common extra- cranial solid tumor in children, is derived from neural crest cells. Nearly half of patients present with metastatic disease, and have 5-year EFS of less than 50%. New approaches with targeted therapy may improve efficacy without increased toxicity. The current review will evaluate three promising targeted therapies, including 131I-metaiodobenzylguanidine (MIBG), a radiopharmaceutical taken up by the human norepinephrine transporter expressed in 90% of neuroblastomas, immunotherapy with monoclonal antibodies targeting the GD2 ganglioside, expressed on 98% of neuroblastoma cells, and inhibitors of ALK, a tyrosine kinase which is mutated or amplified in approximately 10% of neuroblastoma and expressed on the surface of most neuroblastoma cells. Early phase trials have confirmed the activity of 131I-MIBG in relapsed neuroblastoma, with response rates of about 30%, but the technical aspects of administration of large amounts of radioactivity in young children and the limited access have hindered incorporation into treatment of newly diagnosed patients. Anti-GD2 antibodies have also demonstrated activity in relapsed disease, and a recent phase III randomized trial showed a significant improvement in event-free survival for patients receiving chimeric anti-GD2 (ch14.18) combined with cytokines and isotretinoin after myeloablative consolidation therapy. A recently approved small molecule inhibitor of ALK has promising pre-clinical activity for neuroblastoma, and is currently in phase I and II trials. This is the first agent directed to a specific mutation in neuroblastoma, and marks a new step toward personalized therapy for neuroblastoma. Further clinical development of targeted treatments offers new hope for children with neuroblastoma.

Prolonged progression-free survival after consolidating second or later remissions of neuroblastoma with Anti-GD2immunotherapy and isotretinoin: a prospective Phase II study

“…Examples include investigative agents 1 (e.g., fenretinide 37 and crizotinib 38 ), and targeted radiotherapy using 131 I-MIBG or radiolabeled mAbs. 39,40 Immunotherapy with anti-G D2 mAbs might eradicate remaining MRD, as has been documented in patients in first CR/VGPR 23 and as shown now in the current report on second or later CR/VGPR. Success against isolated CNS relapse (Tables 2 and 3), which historically heralded a rapid demise, 41 supports the curative potential of the above strategy.…”

“…44 Greater anti-NB activity is a possibility with new generations of antibody-based immunotherapy 26,45,46 and other targeted therapies. 40 47 Major organ toxicity had to be grade 2 by Common Terminology Criteria for Adverse Events Version 2.0 (CTCAEv2.0), although neutrophil count 500/ml and platelet count 10,000/ml were acceptable. Informed written consents for this trial were obtained following institutional review board rules.…”

Targeted immunotherapy for pediatric solid tumors

“…The mAb ch14.18 is a chimeric mouse-human antibody with a longer half-life than 14G2a, which also showed efficacy in an initial pilot study and a phase II trial in children with recurrent/refractory neuroblastoma. 4,6 Both studies included IL-2 and GM-CSF to enhance ADCC. 6,7 This led to a Children's Oncology Group (COG) phase III study in newly diagnosed high-risk neuroblastoma.…”

“…4,6 Both studies included IL-2 and GM-CSF to enhance ADCC. 6,7 This led to a Children's Oncology Group (COG) phase III study in newly diagnosed high-risk neuroblastoma. In this trial patients were randomized to receive immunotherapy with ch14.18 antibody combined with alternating IL-2 and GM-CSF.…”

Sorafenib treatment in children with relapsed and refractory neuroblastoma: an experience of four cases

“…Many early phase clinical trials have been conducted on small‐molecule inhibitors and antibodies, some of which, including anti‐GD2 antibody and ALK inhibitors, may improve outcome 3. Sorafenib is an orally active inhibitor of multiple kinases, including C‐RAF, B‐RAF, c‐KIT, FLT3, platelet‐derived growth factor receptor (PDGFR)‐ α and ‐ β , and vascular endothelial growth factor receptor (VEGFR)‐1, ‐2, and ‐3 4.…”