# Cell-Selective CpG-STAT3 Inhibitors for Radioimmunotherapy of Malignant Glioma

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2020 · $460,943

## Abstract

Despite multimodal treatments, such as radiation therapy, malignant gliomas (MG) are rapidly fatal. Resistance
of MG to radiation therapy (RT) is a consequence of both intrinsic cancer cell properties and protective
influence of the tumor microenvironment. We previously demonstrated that RT-induced cell death causes the
release of danger signals recruiting Toll-like Receptor-9 (TLR9)-positive myeloid cells which jump-start tumor
vascularization and regrowth. The proangiogenic (rather than immunostimulatory) effects of TLR9 activation
are mediated by NF-κB/IL-6-dependent activation of Signal Transducer and Activator of Transcription (STAT3).
STAT3 is a multifaceted oncogene and a central immune checkpoint regulator activated in cancer cells and in
tumor-associated myeloid cells in patients with MG and with other tumors. It remains an elusive target, with no
FDA-approved direct small molecule STAT3 inhibitors. To overcome this challenge, we previously developed a
strategy to deliver STAT3 siRNA specifically into TLR9-positive myeloid cells and glioma cells, by physically
linking siRNA to TLR9 ligands, CpG oligodeoxynucleotides (ODNs). Our previous preclinical studies
demonstrated that local tumor treatment using CpG-STAT3siRNA silences STAT3 in glioma and other tumor
models, thereby reducing tumor revascularization while stimulating systemic antitumor immunity. We propose
to use a new generation of CpG-STAT3 inhibitors (CSIs) based on STAT3 antisense oligonucleotide (CpG-
STAT3ASO) or STAT3 decoy oligodeoxynucleotide (CpG-STAT3dODN) design to support RT against
recurrent human MG. We propose studies to assess feasibility, pharmacokinetic/pharmacodynamic properties,
efficacy and safety of systemic administration of new CSIs against human and mouse models of MG in vivo.
Our aim is to produce clinically relevant, effective and safe CSI-based strategies capable of overcoming RT
resistance in MG in order to generate long term antitumor immune responses.

## Key facts

- **NIH application ID:** 10002154
- **Project number:** 5R01CA215183-03
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Marcin Kortylewski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $460,943
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10002154

## Citation

> US National Institutes of Health, RePORTER application 10002154, Cell-Selective CpG-STAT3 Inhibitors for Radioimmunotherapy of Malignant Glioma (5R01CA215183-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10002154. Licensed CC0.

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