Abstract LB-092: Survival impact of anti-GD2 antibody response - A phase II ganglioside vaccine trial in relapsed neuroblastoma

Abstract

Abstract Background and Aim: High-risk neuroblastoma (HR-NB) relapse carries a dismal prognosis. Recent experience, however, suggests that cure is possible when remission is achieved with salvage therapy that includes anti-GD2 monoclonal antibody (mAb). The long-term survival and the favorable safety profile of gangliosides GD2 and GD3 vaccine among these patients in a Phase I trial (n=15, Clinical Cancer Res 2014) need to be confirmed. Moreover, the kinetics of seroconversion (mounting anti-vaccine antibody response) and its prognostic impact on survival need to be explored. Patients and Methods: In this Phase II trial (Clinicaltrials.gov NCT00911560), 102 HR-NB patients who achieved complete remission after salvage therapy were enrolled. They received 7 subcutaneous vaccine injections (week 1-2-3-8-20-32-52) plus oral beta-glucan (starting in week 6 at 40 mg/kg/day, 14 days on/14 days off). Each subcutaneous vaccine injection consisted of 30 µg each of GD2 and GD3, lactonized and conjugated to keyhole limpet hemocyanin and mixed with the saponin OPT-821 adjuvant. Serum anti-vaccine antibody titers were quantified by ELISA. Kaplan-Meier statistics and landmark Cox Regression models were used for survival estimates and prognostic impact analyses. Results: Among 102 patients, 63% had one, 21% had 2, and 16% had 3-6 prior disease progressions. 83/101 patients had failed prior anti-GD2 mAb (m3F8, dinutuximab, or naxitamab) therapy before vaccine: one mAb (n=62), two mAbs (n=15), or all three (n=6). Common toxicities were self-limited injection-related local reactions and fever. No pain, neuropathy, or grade 3/4 toxicities occurred during or post treatment. Progression-free survival (PFS) was 44%±5% and overall survival (OS) was 88%±4% at 2 years, and 36%±7% and 70%±8% at 5 years, respectively. Serum anti-GD2 (IgG1 and IgM) and anti-GD3 (IgG1) titers had marked increases following the initiation of beta-glucan at week 6. In univariate analyses, favorable prognostic factors included: one versus ≥2 prior disease progressions (PFS p=0.005, OS p=0.04), none versus any prior anti-GD2 mAb failures (PFS p=0.004, OS p=0.01); and the induction of ≥150 ng/ml anti-GD2-IgG1 titers by week 8 (PFS p=0.02, OS p=0.06). Factors not prognostic included: time to first NB progression, MYCN amplification status, anti-GD2-IgM, anti-GD3-IgG1 or anti-KLH-IgG1 titers, and treatment with anti-GD2 mAb right before vaccine. In multivariate analyses, week 8 anti-GD2-IgG1 titer ≥150 ng/ml yielded a hazard ratio (HR) of 0.41 [0.20, 0.83], p=0.01 for PFS, and HR=0.15 [0.02, 1.12], p=0.06 for OS. The second independent prognostic variable was the number of prior disease progressions (≥2 vs 1), yielding HR of 2.12 [1.26, 3.58], p=0.005 for PFS, and HR=2.77 (1.03, 7.47), p=0.04 for OS. Conclusions: Even with prior disease progressions, anti-GD2 (though not anti-GD3) seroconversion was associated with notable long-term survival among HR-NB patients previously thought to be unsalvageable. A randomized trial to assess the role of beta-glucan in seroconversion is actively accruing patients. Citation Format: Irene Y. Cheung, Nai-Kong V. Cheung, Shakeel Modak, Audrey Mauguen, Ellen Basu, Stephen S. Roberts, Govind Ragupathi, Brian H. Kushner. Survival impact of anti-GD2 antibody response - A phase II ganglioside vaccine trial in relapsed neuroblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-092.