Interstitial Control-Released Polymer Carrying a Targeting Small-Molecule Drug Reduces PD-L1 and MGMT Expression in...

Area of Science:

• Neuro-oncology
• Biomaterials
• Pharmacology

Background:

• Recurrent glioblastoma presents challenges due to incomplete tumor removal, brain edema, and resistance to temozolomide (TMZ) via O6-methylguanine-DNA-methyltransferase (MGMT) and programmed cell death-ligand 1 (PD-L1) expression, leading to immune-cold lesions.
• Existing treatments like Gliadel wafer have limitations in efficacy and safety.
• There is a need for novel therapeutic strategies to improve outcomes in recurrent high-grade glioma.

Purpose of the Study:

• To evaluate the safety and efficacy of Cerebraca wafer, a biodegradable polymer containing (Z)-n-butylidenephthalide (BP), in combination with TMZ for patients with recurrent high-grade glioma.
• To assess the impact of Cerebraca wafer on overall survival (OS), progression-free survival (PFS), and potential mechanisms of action, including overcoming TMZ resistance.

Main Methods:

• An open-label, one-arm, dose-escalation clinical trial (3+3 design) was conducted with four dose cohorts of Cerebraca wafer combined with TMZ.
• 12 patients with recurrent high-grade glioma received Cerebraca wafer implantation.
• In vitro studies were performed on primary cells to determine the IC50 of BP and assess its effects on MGMT, PD-L1, T-cell cytotoxicity, and interferon-gamma (IFN-γ) secretion.

Main Results:

• No drug-related adverse events (AEs) or serious AEs (SAEs) were reported in the 12 patients.
• Patients receiving low-dose Cerebraca wafer with >25% wafer coverage achieved a median OS of 12 months, outperforming historical Gliadel wafer data (6.4 months).
• Patients receiving high-dose Cerebraca wafer demonstrated 100% PFS at six months, with a median OS exceeding 17.4 months.
• In vitro, BP showed significantly lower IC50 against tumor stem cells compared to BCNU, exhibited a synergistic effect with TMZ by reducing MGMT expression, and inhibited PD-L1 expression, enhancing T-cell activity.

Conclusions:

• Cerebraca wafer is safe and well-tolerated in combination with TMZ for recurrent high-grade glioma.
• Cerebraca wafer demonstrates promising efficacy, improving OS and PFS compared to historical controls.
• The therapeutic benefits may stem from re-sensitizing tumors to TMZ and overcoming immune suppression by reducing PD-L1 expression.