Dual Immunostimulatory Pathway Agonism through a Synthetic Nanocarrier Triggers Robust Anti-Tumor Immunity in Murine Glioblastoma.

in Advanced materials (Deerfield Beach, Fla.) by Sophie Lugani, Elias A Halabi, Juhyun Oh, Rainer H Kohler, Hannah M Peterson, Xandra O Breakefield, E Antonio A Chiocca, Miles A Miller, Christopher S Garris, Ralph Weissleder

TLDR

  • The study is looking at how myeloid cells in the brain tumor called glioblastoma (GBM) are not helping the body fight the tumor. The researchers think that small molecules can help myeloid cells fight the tumor. They made a special kind of particle that can deliver these small molecules to the myeloid cells in the GBM. The particles also help the myeloid cells work better to fight the tumor. The study found that the particles helped the myeloid cells work better and the tumor grew less. This could be a new way to treat GBM.

Abstract

Myeloid cells are abundant, create a highly immunosuppressive environment in glioblastoma (GBM), and thus contribute to poor immunotherapy responses. Based on the hypothesis that small molecules can be used to stimulate myeloid cells to elicit anti-tumor effector functions, a synthetic nanoparticle approach is developed to deliver dual NF-kB pathway-inducing agents into these cells via systemic administration. Synthetic, cyclodextrin-adjuvant nanoconstructs (CANDI) with high affinity for tumor-associated myeloid cells are dually loaded with a TLR7 and 8 (Toll-like receptor, 7 and 8) agonist (R848) and a cIAP (cellular inhibitor of apoptosis protein) inhibitor (LCL-161) to dually activate these myeloid cells. Here CANDI is shown to: i) readily enter the GBM tumor microenvironment (TME) and accumulate at high concentrations, ii) is taken up by tumor-associated myeloid cells, iii) potently synergize payloads compared to monotherapy, iv) activate myeloid cells, v) fosters a "hot" TME with high levels of T effector cells, and vi) controls the growth of murine GBM as mono- and combination therapies with anti-PD1. Multi-pathway targeted myeloid stimulation via the CANDI platform can efficiently drive anti-tumor immunity in GBM.

Overview

  • The study aims to investigate the role of myeloid cells in the immunosuppressive environment of glioblastoma (GBM) and their contribution to poor immunotherapy responses. The hypothesis is that small molecules can be used to stimulate myeloid cells to elicit anti-tumor effector functions. A synthetic nanoparticle approach is developed to deliver dual NF-kB pathway-inducing agents into these cells via systemic administration. The study uses synthetic, cyclodextrin-adjuvant nanoconstructs (CANDI) with high affinity for tumor-associated myeloid cells, which are dually loaded with a TLR7 and 8 (Toll-like receptor, 7 and 8) agonist (R848) and a cIAP (cellular inhibitor of apoptosis protein) inhibitor (LCL-161) to dually activate these myeloid cells. The primary objective of the study is to investigate the efficacy of the CANDI platform in driving anti-tumor immunity in GBM.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions, specifically the effects of the CANDI platform on the growth of murine GBM as mono- and combination therapies with anti-PD1. The results show that the CANDI platform potently synergizes payloads compared to monotherapy, activates myeloid cells, fosters a
  • and controls the growth of murine GBM as mono- and combination therapies with anti-PD1. The key findings of the study suggest that multi-pathway targeted myeloid stimulation via the CANDI platform can efficiently drive anti-tumor immunity in GBM.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as they suggest that small molecules can be used to stimulate myeloid cells to elicit anti-tumor effector functions in GBM. The limitations of the study include the use of murine models, which may not fully translate to human GBM. Future research directions could include the development of human-based models to validate the findings, the exploration of other myeloid cell types, and the investigation of the long-term effects of the CANDI platform on the immune system.
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