Neoadjuvant PD1 blockade with laser interstitial thermal therapy for recurrent high-grade glioma

Abstract

Background: While immune checkpoint inhibitors (ICI) induce potent responses against several systemic malignancies, clinical efficacy against high-grade glioma has been limited by immunosuppression, low mutational burden and limited lymphocyte infiltration into tumors. Laser interstitial thermal therapy (LITT) induces coagulative necrosis and disrupts the peritumoral blood-brain barrier (BBB), creating a potentially antigenic milieu. We hypothesized that neoadjuvant and adjuvant ICI would synergize with LITT to potentiate antitumor immune responses and enhance survival.

Methods: This retrospective study is an exploratory case series that includes 9 adult patients with recurrent IDH wild-type glioblastoma (GBM, n = 6), IDH mutant high-grade astrocytoma (n = 2) and H3K27M mutant diffuse midline glioma (n = 1). All patients received neoadjuvant anti-PD1 ICI prior to LITT and most received adjuvant ICI (8/9). Disease burden was followed through radiographic volume segmentation of gadolinium-enhancing disease. Patients were followed for progression-free (PFS) and overall survival (OS).

Results: Patients (age 29-64 years; 7 male, 2 female) had pre-operative mean tumor volumes of 11.15 cm³ (range 2.93-26.09 cm³). Mean ablation volume was 12.08 cm³ (range 5.14-18.60 cm³). There were no perioperative complications. All patients showed an initial increase in gadolinium-enhancing volume after LITT. Seven of 9 (78 %) patients demonstrated subsequent regression in total gadolinium-enhancing volume. Three non-contiguous satellite lesions naïve to laser ablation exhibited complete or near-complete regression in 2 patients. Median PFS was 5.90 months (range 1.00-41.23), and median OS was 9.97 months (range 1.20-41.23).

Conclusions: Combination therapy with neoadjuvant and adjuvant pembrolizumab and LITT is feasible and safe in recurrent high-grade glioma. Responses may be more robust in certain molecular subtypes of glioma. Further studies are needed to investigate this potential synergy.

Keywords: Glioblastoma; Glioma; Immune Checkpoint Inhibitors; Laser Therapy; Neoadjuvant Therapy; Programmed Cell Death Receptor 1; Tumor Microenvironment.