Immunotherapy of Malignant Glioma by Noninvasive Administration of TLR9 Agonist CpG Nano‐Immunoadjuvant

Abstract

Immunotherapy with toll like receptor 9 (TLR9) agonist CpG ODN offers an emergent strategy to treat life-threatening malignant glioma. CpG is typically applied invasively by intracranial and intrathecal administration which induces not only poor compliance and lessened potency but also possibly strong adverse effects and immunotoxicity. Here, it is reported that immunotherapy of murine LCPN glioma is greatly boosted by polymersome-steered intravenous and intranasal brain delivery of CpG. CpG is efficiently loaded in apolipoprotein E peptide-directed polymersomes to give blood-brain barrier permeable and glioma and cervical lymph node-homing CpG nano-immunoadjuvant (t-NanoCpG) which strongly stimulates the maturation of dendritic cells, antigen cross-presentation, and production of proinflammatory cytokines in vivo. Intriguingly, both intravenous and intranasal administration of t-NanoCpG brings about significant survival benefits in murine LCPN glioma-bearing mice while free CpG and nontargeted CpG nano-immunoadjuvant (NanoCpG) afford modest therapeutic effects. Moreover, combination of t-NanoCpG with radiotherapy further boosts the immunotherapeutic effects leading to more improved survival rate of mice. This intelligent brain-permeable nano-immunoadjuvant provides a new, minimally invasive and highly potent strategy for immunotherapy of glioma.

Immunogenic Cell Death Activates the Tumor Immune Microenvironment to Boost the Immunotherapy Efficiency

“…[ 113 ] Unmethylated cytosine‐phosphate‐guanine (CpG), an immunostimulatory nucleic acid, is a powerful toll‐like receptor‐9 (TLR9) agonist to induce a cascade of adaptive and innate immune responses, and it has been widely used as an adjuvant. [ 114 ] CpG can specifically bind to TLR9 to induce the production of cytokines such as IFN‐ γ , IL‐12, IL‐6, TNF‐ α , and increase the level of co‐stimulatory molecules expressed by B cells and DCs. [ 115 ] In particular, clinical trial results have indicated that CpG can enhance T cells responses to boost the antitumor effect when it is used as a single agent or it is combined with antineoplastic therapies.…”

Development of nanotechnology-mediated precision radiotherapy for anti-metastasis and radioprotection

“…Recently, various immunoadjuvant-loaded NPs have been developed to enhance the abscopal effect of RT. 42,432,[514][515][516][517] For example, Patel et al designed bacterial membranecoated NPs (BNPs) to promote RT to elicit systemic antitumor immunity against local tumors and metastatic relapse. 518 The BNPs were composed of four components.…”

Immunology Meets Bioengineering: Improving the Effectiveness of Glioblastoma Immunotherapy

“…This was a redox responsive formulation, which led to the stimulation of pro-inflammatory cytokine production and DC maturation in vivo, as well as the reprogramming of the tumor immune microenvironment by inducing more immunogenic cell death (ICD) (of tumor cells), CD8 + T cells, and activated antigen presentation cells (APCs). Combined use of this “smart” brain-permeable nano-immunoadjuvant with radiotherapy further boosted the anti-cancer effect and improved the survival rate in mice ( Figure 7 ) [ 192 ].…”

“…Abbreviations: ApoE: Apolipoprotein E, IFN-γ: Interferon gamma, TNF-α: Tumor necrosis factor alpha, IL-6: Interleukin 6, CNS: Central nervous system, CLN: Cervical lymph node, PBS: Phosphate buffer saline. Reprinted with permission from [ 192 ].…”