Polyinosinic/Polycytidylic Lipid Nanoparticles Enhance Immune Cell Infiltration and Improve Survival in the Glioblastoma Mouse Model.

in Molecular pharmaceutics by Melanie M T Brüßeler, Alaa Zam, Víctor M Moreno-Zafra, Nadia Rouatbi, Osama W M Hassuneh, Alessia Marrocu, Revadee Liam-Or, Hend Mohamed Abdel-Bar, Adam Alexander Walters, Khuloud T Al-Jamal

TLDR

  • This study investigates whether a special kind of medicine called nanoparticles can help fight a type of brain tumor called glioblastoma. The nanoparticles are made of a special kind of fat called lipids and contain a medicine called doxorubicin. The study found that the nanoparticles helped activate the immune system to fight the tumor and led to better outcomes in mice. The study suggests that this kind of medicine could be used in the future to help fight glioblastoma in humans.

Abstract

Glioblastoma (GBM) immunotherapy is particularly challenging due to the pro-tumorigenic microenvironment, marked by low levels and inactive immune cells. Toll-like receptor (TLR) agonists have emerged as potent immune adjuvants but failed to show improved outcomes in clinical trials when administered as a monotherapy. We hypothesize that a combined nanoparticulate formulation of TLR agonist and immunogenic cell death-inducing drug (doxorubicin) will synergize to induce improved GBM immunotherapy. Lipid nanoparticle (LNP) formulations of the TLR agonists CpG and polyinosinic/polycytidylic (pIpC), with and without Dox, were first prepared, achieving an encapsulation efficiency >75% and a size <140 nm. In vitro studies identified that LNP pIpC was superior to CpG at activating bone marrow-derived immune cell populations (dendritic cells and macrophages) with minimal toxicity. It was also observed that the pIpC formulation can skew macrophage polarization toward the antitumorigenic M1 phenotype and increase macrophage phagocytosis of cancer cells. Upon intratumoral administration, pIpC Dox LNPs led to significant immune cell infiltration and activation. In survival models, the inclusion of Dox into pIpC LNP improved mice survival compared to control. However, addition of Dox did not show significant improvement in mice's survival compared to singly formulated pIpC LNP. This study has illustrated the potential of pIpC LNP formulations in prospective GBM immunotherapeutic regimes. Future studies will focus on optimizing dosage regimen and/or combination with other modalities, including the standard of care (temozolomide), immune checkpoint blockade, or cancer vaccines.

Overview

  • The study aims to investigate the potential of a combined nanoparticulate formulation of TLR agonist and immunogenic cell death-inducing drug (doxorubicin) in improving GBM immunotherapy. The hypothesis is that the combined formulation will synergize to induce improved GBM immunotherapy. The study uses lipid nanoparticle (LNP) formulations of the TLR agonists CpG and polyinosinic/polycytidylic (pIpC), with and without Dox, and evaluates their in vitro and in vivo effects on GBM immunotherapy. The primary objective is to determine the efficacy of the pIpC Dox LNP formulation in improving GBM immunotherapy.

Comparative Analysis & Findings

  • In vitro studies showed that LNP pIpC was superior to CpG at activating bone marrow-derived immune cell populations (dendritic cells and macrophages) with minimal toxicity. The pIpC formulation can skew macrophage polarization toward the antitumorigenic M1 phenotype and increase macrophage phagocytosis of cancer cells. Upon intratumoral administration, pIpC Dox LNPs led to significant immune cell infiltration and activation. In survival models, the inclusion of Dox into pIpC LNP improved mice survival compared to control. However, addition of Dox did not show significant improvement in mice's survival compared to singly formulated pIpC LNP. This suggests that the combination of pIpC and Dox may have a synergistic effect on GBM immunotherapy, but the addition of Dox alone does not significantly improve outcomes.

Implications and Future Directions

  • The study highlights the potential of pIpC LNP formulations in prospective GBM immunotherapeutic regimes. Future studies will focus on optimizing dosage regimen and/or combination with other modalities, including the standard of care (temozolomide), immune checkpoint blockade, or cancer vaccines. The findings suggest that the combination of pIpC and Dox may have a synergistic effect on GBM immunotherapy, but further research is needed to determine the optimal dosage and combination of these agents for clinical use.
Read Full Article