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 PD-1 blockade, tumor injury sites exhibit an increase in tumor infiltrating lymphocytes and

Therapeutic Ultrasound-Enhanced Immune Checkpoint Inhibitor Therapy

“…These findings [13][14][15][16] suggest that HIFU mechanical ablation alone, without the need for adjuvants, is sufficient to enhance ICI therapy for the treatment of cancers that are unresponsive to ICIs. One advantage of HIFU mechanical ablation over HIFU thermal ablation is that tumor fragmentation instead of tumor coagulation may protect TAAs and DAMPs from protein denaturation by excessive heat and stimulate more effective antitumor immune responses [15,16,33,41].…”

“…These studies suggest that the optimal protocol for HIFU thermal ablation-enhanced ICI therapy may depend on the tumor model, the type of adjuvants used, with or without immunotherapy priming, and the HIFU ablation protocol. HIFU thermal ablation as a combination therapy with ICIs has the potential limitation that excessive heat generation by HIFU thermal ablation may induce protein denaturation and inactivate antigen presentation [13]. Meanwhile, HIFU thermal ablation was also reported to increase tumor infiltrated MDSCs and Tregs at both directly treated and distant tumors, leading to inhibition of antitumor immunotherapy [11].…”

“…The clinical applications of ICIs in brain tumors (e.g., glioblastoma and neuroblastoma) have been challenging, potentially because these tumors harbor a "cold" immune microenvironment that lacks requisite T cells and sufficient TAAs and contains high densities of immunosuppressive cell populations [39,40]. One recent study demonstrated that HIFU mechanical ablation combined with silica microshells mechanically disrupted glioblastoma tumors and augmented the efficacy of αPD-1 [13]. The combination of HIFU mechanical ablation with microshells and αPD-1 increased tumor-infiltrating CD8 and IFN-γ + CD8 T cells, prolonged tumor-free survival and protected against tumor rechallenge, suggesting the formation of long-term immune memory against glioblastoma.…”

“…As a promising therapeutic technology, FUS has the unique combined advantages of being noninvasive, nonionizing, nonpharmaceutical, spatially targeted, and deeply penetrating the body. Since 2017, five FUS modalities, including highintensity focused ultrasound (HIFU) thermal ablation [7][8][9][10][11], HIFU hyperthermia [12], HIFU mechanical ablation [13][14][15][16][17], ultrasound-targeted microbubble destruction (UTMD) [18][19][20], and sonodynamic therapy (SDT) [21,22], have been investigated in combination with ICIs for treating solid tumors in mouse models. The enhancement of antitumor immune responses by these FUS modalities demonstrated the great promise of FUS as a transformative cancer treatment modality to improve ICI therapy.…”

Advances in Nanotechnology-Based Immunotherapy for Glioblastoma

“…Wang et al. ( 70 ) used perfluorocarbon (PFC) liquid-filled silica microshells to induce tissue damage through focused ultrasound to generate ICD and combined it with PD-1 blockade to induce a “hot” immune microenvironment and enhance immune checkpoint blockade against advanced tumors. Compared with monotherapy, combination therapy increased the proportion of CD45 leukocytes in the GME by more than 20 times, the proportion of CD8 cytotoxic T cells by more than 100 times, and the expression of IFNγ by more than 200 times, indicating the transition from “cold” to “hot” immune microenvironment.…”