Phase IIb randomized, blinded, controlled trial evaluating neoadjuvant PD-1 blockade combined with A2B5+ glioma stem-like cell lysate-loaded DC vaccine in recurrent glioblastoma (IDH1/2 -).

2059 Background: Our previous study showed A2B5 + glioma stem-like cell lysate-loaded DC vaccine (GSC-DCV) extended survival in recurrent GBM. Additionally, our earlier research indicates that A2B5 + GSCs, enriched with tumor-specific antigens like URGCP, have the potential to activate CD8 + T cells via dendritic cell antigen presentation. Recent research on recurrent GBM suggest aPD-1 mAb neoadjuvant therapy further extends survival. This study is intended to assess the safety and efficacy of this combined therapeutic approach. Methods: Patients with recurrent GBM (IDH1/2 -) post-radiotherapy and chemotherapy were enrolled. All patients received aPD-1 mAbs before surgery. Post-surgery, patients were randomly assigned to the monotherapy arm (aPD-1 mAbs and placebo) or combination therapy arm (aPD-1 mAbs and GSC-DCV), with treatments given every 3-6 weeks until disease progression or intolerable toxicity. The primary endpoint was OS, and secondary endpoints included PFS and trAEs. Results: A total of 21 patients were randomly assigned to the monotherapy (n=11) and combination therapy (n=10) arms. Patient characteristics were well-balanced. The monotherapy arm had a median OS of 8.2 months, while the combination arm showed a significantly longer OS of 22.7 months (HR, 0.2774; 95% CI, 0.0828 to 0.9291, P=0.0376). Multivariate Cox model analysis confirmed the independent prognostic impact of the combination therapy on patients with recurrent GBM (HR, 9.911; 95% CI, 1.520 to 64.623; P=0.016). There was no statistically significant difference in PFS between the two arms. Notably, patients in the combination group experienced a substantial improvement in post-progression survival (PPS) compared to the monotherapy group (7.8 m vs. 1.4 m; P=0.0266). The long survival benefit observed in the combination group was associated with continuous treatment, as cessation led to short-term tumor progression. Subgroup analysis based on tumor burden revealed that the combination therapy was significantly more effective in the low tumor burden cohort (mOS: 23.2 vs. 9.6 months; P=0.0162). No significant difference was observed in the monotherapy group between the two cohorts. High URGCP expression was significantly positively associated with OS in patients undergoing combination therapy (R 2 =0.8608, P=0.0061). Grade 1-2 trAEs were reported in 27.3% of patients in the monotherapy arm and 50.0% in the combination therapy arm. No grade 3 or higher trAEs occurred. Conclusions: The combination therapy has proven to be safe and well-tolerated. Although there was no significant improvement in PFS, patients achieved a sufficiently long OS benefit compared to the monotherapy arm. Notably, the combination therapy was particularly effective in patients with a low tumor burden through long-term, multi-course treatment. Clinical trial information: NCT04888611 .