# Improving Glioma Immunotherapy Efficacy by Regulating Tumor Inflammation

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2023 · $440,000

## Abstract

PROJECT SUMMARY
 Patients diagnosed with glioblastoma (GBM) have a median overall survival of less than two years even
after receiving multimodal therapies. Multiple factors account for this treatment resistance including: 1) Inability
of therapies to cross the blood-brain barrier to reach invading cells; 2) GBM’s molecular heterogeneity and
overlapping escape mechanisms that overcome targeted therapies; 3) Evasive mechanisms that render GBMs
resistant to immunotherapy. Therefore, there is an unmet need for GBM treatment approaches that address
multiple resistance mechanisms.
 The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin
superfamily which was discovered as a transmembrane receptor for the products of nonenzymatic glycation and
oxidation of proteins. RAGE is expressed by glioma cells and is activated by its ligands present in GBM tumor
microenvironment (TME). Activation of RAGE stimulates multiple signaling pathways that promote GBM
progression. Recently, we demonstrated that genetic ablation of intracellular RAGE in gliomas inhibited multiple
oncogenic pathways that not only regulated glioma growth and invasion, but also, improved the efficacy of
immunotherapies by promoted an immunologically “permissive” TME. We also discovered that RAGE ablation
in TME enhances the efficacy of immunotherapy. Based on these observations, we propose to evaluate RAGE
inhibition as a multifaceted therapy for GBM.
 Our central hypothesis is that RAGE inactivation will not only suppress oncogenic pathways that are
important for GBM growth and invasion, but also, enhance responses to immunotherapy. Three independent
aims are proposed. Aim 1 will determine the mechanism of RAGE ablation on enhancing the anti-tumor immune
responses in syngeneic mouse GBM models. Findings from this Aim will uncover novel strategies that could
enhance immunotherapy efficacy in these resistant tumors. Aim 2 will measure the synergistic effects of small
molecule RAGE inhibitors with immunotherapy. In this Aim, we will perform the pre-clinical studies to optimize
the dosing regimen of RAGE inhibitors for future GBM clinical trials. Finally, Aim 3 will Identify mechanisms of
immunotherapy resistance to RAGE ablation. This Aim will identify the mechanisms by which RAGE ligands
such as S100A9 attenuate tumor immune responses.
 Success of any of these aims, which are supported by compelling preliminary data, is expected to lead to the
development of novel and critically needed GBM therapies.

## Key facts

- **NIH application ID:** 10750788
- **Project number:** 1R01NS134116-01
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Behnam Badie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $440,000
- **Award type:** 1
- **Project period:** 2023-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10750788

## Citation

> US National Institutes of Health, RePORTER application 10750788, Improving Glioma Immunotherapy Efficacy by Regulating Tumor Inflammation (1R01NS134116-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10750788. Licensed CC0.

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