Microshell Enhanced Acoustic Adjuvants for Immunotherapy in Glioblastoma

Abstract

A key challenge in immunotherapy for glioblastomas, the most common form of primary adult brain cancer, involves the paucity of immune-stimulatory cells in its “cold” immune-microenvironment. Herein, mechanical acoustic ablation focused by perfluorocarbon (PFC) liquid filled silica microshells is applied to induce immunogenicity via in situ ultrasonic lysis. The inert PFC filled ultra-thin walled silica microshells promote mechanical ablation while aiding in ultrasound guidance. In the presence of programmed cell death protein 1 (PD-1) blockade, tumor injury sites exhibit an increase in tumor infiltrating lymphocytes and interferon-γ (IFN-γ) by 1–2 orders of magnitude. At least 75% of mice grafted with the advanced murine glioblastoma tumors achieve remission when treated with a combination of microshell enhanced ablation and PD-1 blockade, which indicates a synergistic effect. In contrast, none of the mice treated with single therapies achieve durable remission. Likelihood of remission correlated with the abundance of tumor infiltrating lymphocytes (p ' 0.001) and IFN-γ levels (p = 0.001). This study demonstrates a PFC filled ultrathin walled microshell enhanced ablation strategy that induces a “hot” immune-microenvironment and augments efficacy of immune checkpoint blockade against advanced tumors.