epiglucan and Brain-Neoplasms

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).. 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.. 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.. 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.

Topics: Adjuvants, Immunologic; beta-Glucans; Biomarkers; Brain Neoplasms; Cancer Vaccines; Child; Child, Preschool; Disease Progression; Female; Gangliosides; Glioblastoma; Humans; Immunogenicity, Vaccine; Immunoglobulin G; Infant; Lectins, C-Type; Male; Polymorphism, Single Nucleotide; Progression-Free Survival; Time Factors

Most orally administered drugs fail to reach the intracerebral regions because of the intestinal epithelial barrier (IEB) and the blood-brain barrier (BBB), which are located between the gut and the brain. Herein, an oral prodrug delivery system that can overcome both the IEB and the BBB noninvasively is developed for treating gliomas. The prodrug is prepared by conjugating an anticancer drug on β-glucans using a disulfide-containing linker. Following oral administration in glioma-bearing mice, the as-prepared prodrug can specifically target intestinal M cells, transpass the IEB, and be phagocytosed/hitchhiked by local macrophages (Mϕ). The Mϕ-hitchhiked prodrug is transported to the circulatory system via the lymphatic system, crossing the BBB. The tumor-overexpressed glutathione then cleaves the disulfide bond within the prodrug, releasing the active drug, improving its therapeutic efficacy. These findings reveal that the developed prodrug may serve as a gut-to-brain oral drug delivery platform for the well-targeted treatment of gliomas.

Topics: Administration, Oral; Animals; Antineoplastic Agents; beta-Glucans; Blood-Brain Barrier; Brain Neoplasms; Disulfides; Drug Delivery Systems; Endocytosis; Glioma; Intestines; Lymphatic System; Macrophages; Magnetic Resonance Spectroscopy; Mice; Neoplasm Transplantation; Prodrugs; Temozolomide

Topics: Adolescent; beta-Glucans; Brain Neoplasms; Diagnosis, Differential; False Positive Reactions; Germinoma; Humans; Male; Meningitis, Fungal; Proteoglycans