Phase I Trial of Oral Yeast-Derived β-Glucan to Enhance Anti-GD2 Immunotherapy of Resistant High-Risk Neuroblastoma

Abstract

Beta glucans, complex polysaccharides, prime leukocyte dectin-1 and CR3-receptors and enhance anti-tumor cytotoxicity of complement-activating monoclonal antibodies. We conducted a phase I study (clinicaltrials.gov NCT00492167) to determine the safety of the combination of yeast-derived beta glucan (BG) and anti-GD2 murine monoclonal antibody 3F8 in patients with relapsed or refractory high-risk neuroblastoma. Patients received intravenous 3F8 (fixed dose of 10 mg/m2/day × 10 days) and oral BG (dose-escalated from 10–200 mg/kg/day × 17 days in cohorts of 3–6 patients each). Forty-four patients completed 141 cycles. One patient developed DLT: transient self-limiting hepatic transaminase elevation 5 days after starting BG (120 mg/kg/day). Overall, 1, 3, 12 and 24 evaluable patients had complete response, partial response, stable and progressive disease, respectively, at the end of treatment. Positive human anti-mouse antibody response and dectin-1 rs3901533 polymorphism were associated with better overall survival. BG dose level and serum BG levels did not correlate with response. Progression-free and overall survival at 2 years were 28% and 61%, respectively. BG lacked major toxicity. Treatment with 3F8 plus BG was associated with anti-neuroblastoma responses in patients with resistant disease. Although the maximal tolerated dose for yeast BG was not reached, considering the large volume of oral BG, we recommended 40 mg/kg/day as the phase II dose.

An important polysaccharide from fermentum

“…Also, clinical trials can determine the safety of new drugs. To determine the safety of Fermentum-derived β-polysaccharide for the treatment of patients with relapsed or refractory high-risk neuroblastoma, Cardenas et al made Fermentum β-polysaccharide into an oral drug, and 44 patients had varying degrees of relief from tumour symptoms after 141 cycles of the drug ( Cardenas et al, 2021 ). This is certainly good news for the widespread use of Fermentum β-polysaccharide-related drugs in the future.…”

Advances in the Immunomodulatory Properties of Glycoantigens in Cancer

“…However, the immunomodulatory properties of the targeted CLR must be considered to secure the induction of an inflammatory antitumor immune response. Sometimes, the immune regulatory properties of CLRs can be overridden when they are targeted in combi-nation with adjuvants such as TLR ligands [229,230] or TACA-specific antibodies [231,232]. In some cases, the induction of tolerance can be reverted with coinjection of anti-CD40 antibodies to activate DCs and to inhibit tumour growth [233,234].…”

Effect of Oral β-Glucan on Antibody Response to Ganglioside Vaccine in Patients With High-Risk Neuroblastoma

“…The safety and adjuvant effect when given orally was demonstrated in a phase 1 trial . After oral administration to patients, β-glucan was measurable in the blood . Previous preclinical studies found β-glucan localizing in macrophages and transported to the spleen, the lymph nodes, and the bone marrow .…”

“…We tested a special gel formulation of yeast-erived β-glucan in mice and were able to show a strong adjuvant effect in enhancing antiganglioside antibody response . The safety and adjuvant effect when given orally was demonstrated in a phase 1 trial . After oral administration to patients, β-glucan was measurable in the blood .…”

“…A gel formulation of yeast β-glucan was first tested as an oral adjuvant in a phase 1 trial and evaluated for efficacy in a phase 2 ganglioside vaccine study in patients with high-risk neuroblastoma (HR-NB) who had prior disease progression . In the phase 2 study, the association of antibody titer with dectin-1 SNP highlighted a connection between oral β-glucan and the dendritic cells . The addition of oral β-glucan was associated with a 4-fold higher peak anti-GD2 IgG1 antibody titer when compared with prior vaccine trials with no β-glucan .…”