Anti-GD2 monoclonal antibody (MoAb) combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown efficacy against neuroblastoma (NB). Prognostic variables that could influence clinical outcome were explored.
Patients and methods:
One hundred sixty-nine children diagnosed with stage 4 NB (1988 to 2008) were enrolled onto consecutive anti-GD2 murine MoAb 3F8 ± GM-CSF ± 13-cis-retinoic acid (CRA) protocols after achieving first remission (complete remission/very good partial remission). Patients enrolled in regimen A (n = 43 high-risk [HR] patients) received 3F8 alone; regimen B (n = 41 HR patients), 3F8 + intravenous GM-CSF + CRA, after stem-cell transplantation (SCT); and regimen C (n = 85), 3F8 + subcutaneous GM-CSF + CRA, 46 of 85 after SCT, whereas 28 of 85 required additional induction therapy and were deemed ultra high risk (UHR). Marrow minimal residual disease (MRD) was measured by quantitative reverse transcription polymerase chain reaction. Survival probability was calculated by the Kaplan-Meier method, and prognostic variables were analyzed by multivariate Cox regression model.
At 5 years from the start of immunotherapy, progression-free survival (PFS) improved from 44% for HR patients receiving regimen A to 56% and 62% for those receiving regimens B and C, respectively. Overall survival (OS) was 49%, 61%, and 81%, respectively. PFS and OS of UHR patients were 36% and 75%, respectively. Relapse was mostly at isolated sites. Independent adverse prognostic factors included UHR (PFS) and post-cycle two MRD (PFS and OS), whereas the prognostic factors for improved outcome were missing killer immunoglobulin-like receptor ligand (PFS and OS), human antimouse antibody response (OS), and regimen C (OS).
Retrospective analysis of consecutive trials from a single center demonstrated that MoAb 3F8 + GM-CSF + CRA is effective against chemotherapy-resistant marrow MRD. Its positive impact on long-term survival can only be confirmed definitively by randomized studies.
"Because miRNA expression patterns in human cancers are tissue-specific, serum miRNA profiles at diagnosis may have prognostic value for metastatic potential to CNS or other organs (Lu et al., 2005; Toiyama et al., 2013). This is an important clinical question, since CNS relapse is now increasingly common among neuroblastoma patients who survive their Stage 4 systemic disease (Cheung et al., 2012). With the exception of miR-21, all downregulated miRNA sequence families in our study (miR-22, miR-29a, miR-143, miR-199a-1–3p, and miR-199a-1–5p) have previously been shown to be associated with suppression or inhibition of metastases in various tumors. "
"It binds specifically to the pentasaccharide epitope on GD2. Phase II clinical data have demonstrated that 3F8 when combined with the cytokine GM-CSF can significantly improve the survival of high-risk stage 4 children with metastatic neuroblastoma (14). Murine 3F8 was more recently humanized (hu3F8) based on complementarity determining region (CDR) grafting (13), and is currently in Phase I clinical trials (clinical trials.gov "
[Show abstract][Hide abstract] ABSTRACT: Disialoganglioside GD2 is an important target on several pediatric and adult cancer types including neuroblastoma, retinoblastoma, melanoma, small-cell lung cancer, brain tumors, sarcomas, and cancer stem cells. We have utilized structural and computational methods to refine the framework of humanized monoclonal antibody 3F8, the highest affinity anti-GD2 antibody in clinical development. Two constructs (V3 and V5) were designed to enhance stability and minimize potential immunogenicity. Construct V3 contained 12 point mutations and had higher thermal stability and comparable affinity and in vitro tumor cells killing as the parental hu3F8. Construct V5 had nine point mutations to minimize potential immunogenicity, but resulted in weaker thermal stability, weaker antigen binding, and reduced tumor killing potency. When construct V3 was combined with the single point mutation HC:G54I, the resulting V3-Ile construct had enhanced stability, antigen binding, and a nearly sixfold increase in tumor cell killing. The resulting product is a lead candidate for clinical development for the treatment of GD2-positive tumors.
Frontiers in Immunology 08/2014; 5:372. DOI:10.3389/fimmu.2014.00372
"IL-2 and GM-CSF were shown to enhance ADCC in vitro by activating cytotoxic NK cells and neutrophils (160, 165, 166). When combined with the cytokine GM-CSF and 13-cis-retinoic acid, 3F8 induced >60% long-term survival among high-risk patients with metastatic disease, treated at first remission (167). MAb 3F8 was recently humanized (hu3F8) (168) and is currently in Phase I trials (157). "
[Show abstract][Hide abstract] ABSTRACT: Neuroblastoma (NB), accounting for 10% of childhood cancers, exhibits aberrant cell-surface glycosylation patterns. There is evidence that changes in glycolipids and protein glycosylation pathways are associated to NB biological behavior. Polysialic acid (PSA) interferes with cellular adhesion, and correlates with NB progression and poor prognosis, as well as the expression of sialyltransferase STX, the key enzyme responsible for PSA synthesis. Galectin-1 and gangliosides, overexpressed and actively shedded by tumor cells, can modulate normal cells present in the tumor microenvironment, favoring angiogenesis and immunological escape. Different glycosyltransferases are emerging as tumor markers and potential molecular targets. Immunotherapy targeting disialoganglioside GD2 rises as an important treatment option. One anti-GD2 antibody (ch14.18), combined with IL-2 and GM-CSF, significantly improves survival for high-risk NB patients. This review summarizes our current knowledge on NB glycobiology, highlighting the molecular basis by which carbohydrates and protein-carbohydrate interactions impact on biological behavior and patient clinical outcome.
Frontiers in Oncology 07/2014; 4:114. DOI:10.3389/fonc.2014.00114
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