Irreversible Electroporation and Beta-Glucan-Induced Trained Innate Immunity for Treatment of Pancreatic Ductal Adenocarcinoma: A Phase II Study.

Abstract

Irreversible electroporation (IRE) has augmented the effects of certain immunotherapies in pancreatic ductal adenocarcinoma (PDA). Yeast-derived particulate beta-glucan induces trained innate immunity and successfully reduced murine pancreatic cancer burden. This is a phase II study to test the hypothesis that IRE may augment beta-glucan-induced trained immunity in patients with PDA. In this phase II clinical trial (NCT03080974), surgical ablative IRE was performed on clinical stage III PDA followed by oral beta-glucan administration for 12 months or until disease recurrence. Peripheral blood was taken preoperative, 14 days, and every 3 months and was evaluated by mass cytometry and compared with patients who received IRE alone. Thirty consecutive patients with preoperative clinical stage III PDA were treated with IRE and then initiated on oral beta-glucan postoperatively were compared with 20 patients treated with IRE alone. There were no dose-limiting toxicities with oral beta-glucan, and compliance with therapy was 96% in all patients. Seven patients (23%) developed grade 3 or 4 treatment-related adverse events at 90 days; none required a dose modification of oral beta-glucan. A median disease-free interval (DFI) was 18 months (range 6 to 48 months), with a median overall survival (OS) of 32.5 months (range 4 to 53 months). At 12 months post-IRE, immunophenotyping was demonstrated a significant effect with improvement in the IRE-beta-glucan-treated group. This also resulted in a significant decrease on naive CD4 and CD8 T cells with increased CD4 and CD8 terminal effector cells in the IRE-beta-glucan-treated group, which correlated with a significant improvement in DFI and OS (p = 0.001). Combined beta-glucan with IRE-ablated PDA tumor cells elicited a potent trained response and augmented antitumor functionality at 12 months post-IRE, which translated into an improved DFI and OS.