title: Key role for myeloid cells: phase II results of anti-G(D2) antibody 3F8 plus granulocyte-macrophage colony-stimulating factor for chemoresistant osteomedullary neuroblastoma.
abstract: Anti-G(D2) murine antibody 3F8 plus subcutaneously (sc) administered granulocyte-macrophage colony-stimulating factor (GM-CSF) was used against primary refractory neuroblastoma in metastatic osteomedullary sites. Large study size and long follow-up allowed assessment of prognostic factors in a multivariate analysis not reported with other anti-G(D2) antibodies. In a phase II trial, 79 patients without prior progressive disease were treated for persistent osteomedullary neuroblastoma documented by histology and/or metaiodobenzyl-guanidine (MIBG) scan. In the absence of human antimouse antibody, 3F8 + scGM-CSF cycles were repeated up to 24 months. Minimal residual disease (MRD) in bone marrow was measured by quantitative reverse transcription-polymerase chain reaction pre-enrollment and post-cycle #2, before initiation of 13-cis-retinoic acid. Study endpoints were: (i) progression-free survival (PFS) compared with the predecessor trial of 3F8 plus intravenously administered (iv) GM-CSF (26 patients) and (ii) impact of MRD on PFS. Using all 105 patients from the two consecutive 3F8 + GM-CSF trials, prognostic factors were analyzed by multivariate Cox regression model. Complete response rates to 3F8 + scGM-CSF were 87% by histology and 38% by MIBG. Five-year PFS was 24 ± 6%, which was significantly superior to 11 ± 7% with 3F8 + ivGM-CSF (p = 0.002). In the multivariate analysis, significantly better PFS was associated with R/R or H/R FCGR2A polymorphism, sc route of GM-CSF and early MRD response. MYCN amplification was not prognostic. Complement consumption was similar with either route of GM-CSF. Toxicities were manageable, allowing outpatient treatment. 3F8 + scGM-CSF is highly active against chemoresistant osteomedullary neuroblastoma. MRD response may be an indicator of tumor sensitivity to anti-G(D2) immunotherapy. Correlative studies highlight the antineoplastic potency of myeloid effectors.
authors.affiliation: Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Nai-Kong V
authors.initials: NK
authors.lastname: Cheung
authors.forename: Irene Y
authors.initials: IY
authors.lastname: Cheung
authors.forename: Kim
authors.initials: K
authors.lastname: Kramer
authors.forename: Shakeel
authors.initials: S
authors.lastname: Modak
authors.forename: Deborah
authors.initials: D
authors.lastname: Kuk
authors.forename: Neeta
authors.initials: N
authors.lastname: Pandit-Taskar
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Chamberlain
authors.forename: Irina
authors.initials: I
authors.lastname: Ostrovnaya
authors.forename: Brian H
authors.initials: BH
authors.lastname: Kushner
mesh_terms: D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D005732:Gangliosides / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007223:Infant; D015474:Isotretinoin / Q000627:therapeutic use; D008297:Male; D022423:Myeloid Cells / Q000187:drug effects* / Q000473:pathology; D009367:Neoplasm Staging; D018365:Neoplasm, Residual / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D009447:Neuroblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D015996:Survival Rate; D055815:Young Adult
chemical_list: C419226:3F8 antibody; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D005732:Gangliosides; D007074:Immunoglobulin G; C019403:ganglioside, GD2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015474:Isotretinoin
keywords: FCGR2A polymorphism; immunotherapy; myeloid effectors