Survival Impact of Anti-GD2 Antibody Response in a Phase II Ganglioside Vaccine Trial Among Patients With High-Risk Neuroblastoma With Prior Disease Progression

Abstract

Purpose: Anti-GD2 monoclonal antibody (mAb) has proven efficacy in high-risk neuroblastoma (HR-NB). A small phase I GD2/GD3 vaccine trial (n = 15) described long-term survival and a favorable safety profile among patients with a history of disease progression (PD). The kinetics of mounting antibody response to vaccine and its prognostic impact on survival are now investigated in a phase II study (ClinicalTrials.gov identifier: NCT00911560).

Patients and methods: One hundred two patients with HR-NB who achieved remission after salvage therapies were enrolled in this trial. They received seven subcutaneous injections of GD2/GD3 vaccine spanning 1 year plus oral β-glucan starting at week 6 after the third dose of vaccine. Serum anti-vaccine antibody titers were quantified by enzyme-linked immunosorbent assay. Single nucleotide polymorphisms (SNPs) were determined by quantitative polymerase chain reaction. Kaplan-Meier and landmark Cox Regression models were used for survival estimates.

Results: Patients had a history of one (63%), two (21%), or three to six (16%) episodes of PD. 82% of them progressed following anti-GD2 mAb (m3F8/dinutuximab/naxitamab) therapy. Vaccine-related toxicities were self-limited injection-associated local reactions and fever without any > grade 3 toxicities. The progression-free survival (PFS) was 32% ± 6%, and the overall survival (OS) was 71% ± 7% at 5 years. Serum anti-GD2 (immunoglobulin G1 [IgG1] and IgM) and anti-GD3 (IgG1) titers showed notable increases following the initiation of β-glucan at week 6. There was an association between IgG1 titer and SNP rs3901533 of dectin-1, the β-glucan receptor. Multivariable analyses showed that anti-GD2-IgG1 titer ≥ 150 ng/mL by week 8 was associated with favorable PFS and OS, while having prior episodes of PD and the time from last PD to vaccine were associated with PFS.

Conclusion: GD2/GD3 vaccine plus β-glucan elicited robust antibody responses in patients with HR-NB with prior PD. Higher anti-GD2-IgG1 titer was associated with improved survival.

Trial registration: ClinicalTrials.gov NCT00911560 NCT01141491.

Figures

FIG 1.

Survival outcome after vaccine therapy among 102 patients with high-risk neuroblastoma with prior disease progressions (PDs); progression-free survival (PFS) and overall survival (OS) (A); PFS (B) and OS (C) according to the number of episodes of PD prior to achieving CR and study enrollment; PFS (D) and OS (E) with respect to having successful anti-GD2 monoclonal antibody (m3F8, dinutuximab, or naxitamab) before their last PD; and PFS (F) and OS (G) according to the duration of response to last salvage therapy (≥ 12 m to vaccine). Survival time started from the first dose of vaccine. The shaded areas represent 95% CIs.

FIG 2.

Antibody titer response during vaccine treatment among 101 patients with high-risk neuroblastoma with prior PD. One patient was excluded from this analysis because of progression before receiving β-glucan. β-glucan was initiated from week 6 to the end of vaccine (dose #7 or PD); number of each bar denotes dose #, and number in brackets denotes sample size; antibody titers were quantified by ELISA and expressed as mean + SEM; *P ≤ .05, **P ≤ .01, and ***P ≤ .001 by Wilcoxon signed-rank tests. During vaccine therapy: Anti-GD2-IgG1 titer (A), anti-GD3-IgG1 (C), and anti-GD2-IgM (D); persistence of anti-GD2-IgG1 titer among 62 patients who completed seven doses of vaccine therapy and off β-glucan (B). Anti-GD2-titer of six patients with melanoma receiving a comparable vaccine treatment that did not include oral β-glucan (E). PD, disease progression.

FIG 3.

PFS (A) and OS (B) by induction of anti-GD2-IgG1 titer (≥ 150 ng/mL) by week 8, PFS (C) and OS (D) by anti-GD3-IgG1 titer by week 8, and PFS (E) and OS (F) by anti-GD2-IgM titer by week 8. Titer was dichotomized using the third quartile as high titer. One patient was excluded for this analysis because of PD before receiving β-glucan at week 6. Survival time started from week 8 of vaccine. The shaded areas represent 95% CIs. OS, overall survival; PFS, progression-free survival.

FIG 4.

Association between antibody titer and SNP rs3901533 of dectin-1 (C-type lectin domain family 7 member A) polymorphism (N = 101). Antibody titer for individual patient was measured from the initiation of β-glucan at week 6 to the end of vaccine treatment or disease progression. Average antibody titer over time was tabulated for each patient. Statistics was performed using Kruskal-Wallis test. One patient was excluded from this analysis because of progression before receiving β-glucan. Association was tested in anti-GD2-IgG1 (A), anti-GD3-IgG1 (B), anti-GD2-IgM (C), and anti-KLH-IgG1 (D). KLH, keyhole limpet hemocyanin; SNP, single nucleotide polymorphism.

FIG A1.

Anti-GD2-IgG1 titer by week 8 did not correlate with the week 8 titers of anti-GD3-IgG1 (A), anti-GD2-IgM (B), and anti-KLH-IgG1 (C). KLH, keyhole limpet hemocyanin; R, correlation coefficient.

FIG A2.

No association was observed between anti-GD2-IgG1 titer with SNP rs7309123 (A) and rs16910526 of dectin-1 polymorphism (B) (N = 101). Antibody titer for individual patients was measured from the initiation of β-glucan at week 6 to the end of vaccine treatment or disease progression. Average antibody titer over time was tabulated for each patient. Statistics was performed using Kruskal-Wallis test. One patient was excluded from this analysis because of progression before receiving β-glucan. SNP, single nucleotide polymorphism.