Key role for myeloid cells: Phase II results of anti-GD2 antibody 3F8 plus granulocyte-macrophage colony-stimulating factor for chemoresistant osteomedullary neuroblastoma Journal Article

   

Authors:	Cheung, N. K. V.; Cheung, I. Y.; Kramer, K.; Modak, S.; Kuk, D.; Pandit-Taskar, N.; Chamberlain, E.; Ostrovnaya, I.; Kushner, B. H.
Article Title:	Key role for myeloid cells: Phase II results of anti-GD2 antibody 3F8 plus granulocyte-macrophage colony-stimulating factor for chemoresistant osteomedullary neuroblastoma
Abstract:	Anti-GD2 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-GD2 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-GD2 immunotherapy. Correlative studies highlight the antineoplastic potency of myeloid effectors. What's New? In high-risk neuroblastoma, persistence of osteomedullary metastases forebodes poor outcome. Here, in a phase II trial, anti-GD2 murine antibody 3F8 plus subcutaneously-administered granulocyte-macrophage colony-stimulating factor (GM-CSF) was used against primary refractory neuroblastoma in metastatic osteomedullary sites. The experience documents activity against histologically and/or radiologically-visible chemoresistant neuroblastoma. Large study size and lengthy follow-up allow use of prognostic variables (minimal residual disease, MYCN, Fcγ receptors, KIR genotypes of natural killer cells) in a multivariate analysis not described with other anti-GD2 antibodies. Correlative studies highlight the anti-neoplastic potency of myeloid effectors rather than lymphocytes, usually the focus in the immunotherapy of solid tumors. © 2014 UICC.
Keywords:	immunotherapy; fcgr2a polymorphism; myeloid effectors
Journal Title:	International Journal of Cancer
Volume:	135
Issue:	9
ISSN:	0020-7136
Publisher:	John Wiley & Sons
Date Published:	2014-11-01
Start Page:	2199
End Page:	2205
Language:	English
DOI:	10.1002/ijc.28851
PROVIDER:	scopus
PUBMED:	24644014
PMCID:	PMC4292931
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84906234428&partnerID=40&md5=12b1f838e1c3790d039abaf08ccbbbd8
Notes:	Export Date: 2 September 2014 -- CODEN: IJCNA -- Source: Scopus

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