Immune Checkpoint Inhibition in GBM Primed with Radiation by Engineered Extracellular Vesicles

Abstract

The lack of safe and effective delivery across the blood-brain barrier and the profound immune suppressive microenvironment are two main hurdles to glioblastoma (GBM) therapies. Extracellular vesicles (EVs) have been used as therapeutic delivery vehicles to GBM but with limited efficacy. We hypothesized that EV delivery to GBM can be enhanced by (i) modifying the EV surface with a brain-tumor-targeting cyclic RGDyK peptide (RGD-EV) and (ii) using bursts of radiation for enhanced accumulation. In addition, EVs were loaded with small interfering RNA (siRNA) against programmed cell death ligand-1 (PD-L1) for immune checkpoint blockade. We show that this EV-based strategy dramatically enhanced the targeting efficiency of RGD-EV to murine GBM, while the loaded siRNA reversed radiation-stimulated PD-L1 expression on tumor cells and recruited tumor-associated myeloid cells, offering a synergistic effect. The combined therapy significantly increased CD8+ cytotoxic T cells activity, halting tumor growth and prolonging animal survival. The selected cell source for EVs isolation and the presented functionalization strategy are suitable for large-scale production. These results provide an EV-based therapeutic strategy for GBM immune checkpoint therapy which can be translated to clinical applications.

Comprehensive Characterization of a Novel E3-Related Gene Signature With Implications in Prognosis and Immunotherapy of Low-Grade Gliomas

“…The immune activity and stromal activity were remarkably elevated in the high-risk group, which once again reiterated the heterogeneity of the glioma TIME between the two groups. Determining the roles of the signature genes in TIME cell infiltration heterogeneity will be beneficial to better understand the mechanisms of the TIME antitumor immune response and developing novel immunotherapy strategies ( Kim et al, 2022 ; Ogino et al, 2022 ; Tian et al, 2022 ).…”

Recent Advances and Challenges in Cancer Immunotherapy

“…In glioblastoma, overcoming the TME physical barrier is also being explored. One group combined brain-tumor-targeted peptide-coated extracellular vesicles, loaded with small interfering RNA (siRNA) against PD-L1, and then delivered them with bursts of radiation therapy [ 194 ]. Dual inhibition of PI3K/mTOR pathway combined with the microtubule targeting chemotherapy, paclitaxel, along with ICI, induced sustainable DC, T cell and NK responses, both locally in the TME and systemically [ 195 ].…”

Brain‐targeting drug delivery systems

“…Furthermore, RT has the potential to alter the immune environment and sensitize less immunogenic tumors to ICB. RVG-engineered exosomes (RGD-EV) was developed to deliver siRNA against PD-L1 to GBM (Tian et al, 2022). The results showed that short pulse radiation significantly improved the targeting efficiency of RGD-EVs to brain tumors and their micro-environment, and effectively attenuated radiation-induced tumor-associated myeloid cells and PD-L1 expression on tumor cells.…”