This study initially evaluated the safety and feasibility of intraoperative and postoperative local administration of immune checkpoint inhibitors nivolumab and ipilimumab in patients with recurrent high-grade gliomas (rHGG), and discovered that B7-H3 overexpression correlates with poorer survival outcomes.
Literature Overview
The article "Intracranial administration of anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors in patients with recurrent high-grade glioma" published in Neuro-Oncology reviews the challenges in rHGG treatment and potential roles of immune checkpoint inhibitors. It highlights B7-H3 as an immune checkpoint protein with prognostic value and compares the efficacy and safety of intraoperative versus postoperative local administration strategies, providing a foundation for future exploration of intracranial delivery methods.
Background Knowledge
High-grade gliomas (HGG) are among the most common malignant central nervous system tumors, with glioblastoma (GBM) having extremely poor prognosis (median survival: 14.6 months). Despite breakthroughs achieved by systemic immune checkpoint blockade (ICB) in various cancers, GBM shows limited response, potentially due to blood-brain barrier restricting drug penetration. This study explores direct intracranial administration (iCer and iCav) combined with Ommaya reservoir for postoperative repeated dosing, while assessing correlations between PD-L1/B7-H3 expression and survival outcomes. The findings provide novel directions for localized immunotherapy in rHGG and support the development of B7-H3-targeted treatments.
Research Methods and Experiments
This study enrolled 44 rHGG patients divided into two treatment cohorts (cohort 4 and cohort 7). All patients received intravenous nivolumab (10 mg) pre-surgery, followed by maximal safe resection. During surgery, nivolumab (10 mg) and ipilimumab (5 mg) were directly injected into brain tissue. Postoperatively, cohort 4 received intraventricular nivolumab at varying doses while cohort 7 received combined nivolumab/ipilimumab therapy. The study assessed treatment-related adverse events (TRAE), progression-free survival (PFS), and overall survival (OS), with molecular marker analysis (B7-H3, PD-L1 expression) and cytokine dynamics monitoring in cerebrospinal fluid (CSF).
Key Conclusions and Perspectives
Research Significance and Prospects
This study establishes the safety profile and survival benefits of intracranial local administration of nivolumab and ipilimumab in rHGG patients while demonstrating B7-H3's potential as a biomarker. Future research should explore higher dosages or combination with other immunomodulators to enhance therapeutic efficacy, and further characterize localized immune microenvironment dynamics.
Conclusion
This study demonstrates the feasibility and safety of intraoperative and postoperative local administration of nivolumab and ipilimumab in rHGG patients. B7-H3 expression levels significantly impact survival prognosis, offering new insights into mechanisms of immunotherapy resistance. Although dose-escalation didn't yield significant survival improvements, prolonged OS compared to historical controls suggests localized immune modulation may enhance outcomes. Future studies should optimize administration protocols and biomarker screening strategies to improve immunotherapy efficacy in rHGG. These findings provide clinical evidence for personalized immunotherapy approaches in rHGG and establish foundational methodology for localized brain tumor delivery techniques.
