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Activation of peripheral-blood granulocytes is strongly correlated with patient outcome after immunotherapy with anti-GD2 monoclonal antibody and granulocyte-macrophage colony-stimulating factor.

ABSTRACT: Adjuvant therapy using anti-GD2 monoclonal antibody and granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown treatment success for patients with high-risk neuroblastoma (NB). Although there is ample evidence on how the antibody targets NB, in vivo contribution by GM-CSF remains unclear. This report investigates granulocyte activation and its correlation with treatment outcome.Patients enrolled onto NCT00072358 received multiple treatment cycles, each consisting of anti-GD2 antibody 3F8 plus subcutaneous (SC) GM-CSF. Peripheral-blood (PB) samples from 151 patients were collected on day 0 and day 4 of cycle 1. PB from a subgroup of 35 patients had intravenous (IV) instead of SC GM-CSF during cycle 4. Samples were analyzed by flow cytometry for CD11a, CD63, CD87, and CD11b and its activation epitope CBRM1/5.Comparing cycle 1 day 4 PB samples with day 0 PB samples, five of five activation marker-positive granulocytes were significantly higher. The change in frequency and mean fluorescence intensity of CBRM1/5-positive granulocytes correlated with progression-free survival (PFS; P = .024 and P = .008, respectively). A multivariable analysis identified increasing CBRM1/5-positive granulocytes and missing killer immunoglobulin-like receptor ligand as positive independent prognostic factors for PFS, whereas second-line cyclophosphamide-based therapy before protocol entry negatively influenced outcome. Thirty-five patients who received SC GM-CSF at cycle 1 and IV GM-CSF at cycle 4 had significantly less CBRM1/5 activation after IV GM-CSF. In contrast, 63 patients who received SC GM-CSF at both cycles had comparable CBRM1/5 activation.GM-CSF-induced granulocyte activation in vivo is associated with improved patient outcome. This activation was more apparent when GM-CSF was given by the SC route instead of IV route.

SUBMITTER: Cheung IY

PROVIDER: S-EPMC3269968 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Activation of peripheral-blood granulocytes is strongly correlated with patient outcome after immunotherapy with anti-GD2 monoclonal antibody and granulocyte-macrophage colony-stimulating factor.

Cheung Irene Y IY Hsu Katharine K Cheung Nai-Kong V NK

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20111227 4

<h4>Purpose</h4>Adjuvant therapy using anti-GD2 monoclonal antibody and granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown treatment success for patients with high-risk neuroblastoma (NB). Although there is ample evidence on how the antibody targets NB, in vivo contribution by GM-CSF remains unclear. This report investigates granulocyte activation and its correlation with treatment outcome.<h4>Patients and methods</h4>Patients enrolled onto NCT00072358 received multiple treatmen ...[more]

PMID: 22203761

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Project description:Importance:Chimeric and murine anti-GD2 antibodies are active against neuroblastoma, but the development of neutralizing antibodies can compromise efficacy. To decrease immunogenicity, hu3F8, a humanized anti-GD2 antibody, was constructed. Objective:To find the maximum-tolerated dose of hu3F8 with granulocyte-macrophage colony-stimulating factor. Design, Setting, and Participants:This phase 1 clinical trial used a 3?+?3 dose-escalation design in a single referral center (Memorial Sloan Kettering Cancer Center, New York, New York). Participants were enrolled from December 24, 2012, through May 3, 2016, with follow-up and analyses through February 28, 2018. Eligibility criteria included older than 1 year and resistant or recurrent neuroblastoma regardless of the number or kinds of prior treatments. All 57 participants met the eligibility criteria, received treatment according to the protocol, and were included in all analyses. Interventions:Treatment cycles were monthly, if human antihuman antibody remained negative. Each cycle comprised hu3F8 infused intravenously for 30 minutes on Monday, Wednesday, and Friday as well as granulocyte-macrophage colony-stimulating factor administered subcutaneously daily from 5 days before infusion through the last day of infusion. After cycle 2, hu3F8 was increased to the highest dose level that had been confirmed as safe. Main Outcomes and Measures:Toxicity, pharmacokinetics, immunogenicity, and disease response. Results:Of the 57 participants, 34 (60%) were male and 23 (40%) were female (male-to-female ratio of 1.5), with a median (range) age of 6.8 (2.4-31.3) years at enrollment and a median (range) time of 3.1 (0.6-9.0) years since initial chemotherapy. Participants received a median (range) of 4 (1-15) cycles. Treatment was outpatient with reversible neuropathic pain and without unexpected toxic effects. No maximum-tolerated dose was identified. Dose escalation was associated with increased serum levels and proceeded through dosage of 9.6 mg/kg/cycle (approximately 288 mg/m2), which is more than 2.5?times?higher than the standard dosage of 75 mg/m2/cycle or 100 mg/m2/cycle of dinutuximab and m3F8. Human antihuman antibody positivity developed in 5 of 57 patients (9%) after cycle 1, including in 1 of 10 patients (10%) not previously treated with anti-GD2 antibody and in 4 of 47 patients (9%) previously exposed to 1 or 2 anti-GD2 antibodies. Antineuroblastoma activity included major responses associated with higher dosing and prolonged progression-free survival despite a history of relapses. Conclusions and Relevance:This phase 1 clinical trial found hu3F8 to be associated with modest toxic effects, low immunogenicity, and substantial antineuroblastoma activity; phase 2 trials are in progress. Trial Registration:ClinicalTrials.gov identifier: NCT01757626.

Project description: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.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.

Dataset Information

Activation of peripheral-blood granulocytes is strongly correlated with patient outcome after immunotherapy with anti-GD2 monoclonal antibody and granulocyte-macrophage colony-stimulating factor.

Publications

Activation of peripheral-blood granulocytes is strongly correlated with patient outcome after immunotherapy with anti-GD2 monoclonal antibody and granulocyte-macrophage colony-stimulating factor.

Similar Datasets

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