# Improving IL12 Immunogene Therapy for Glioblastoma Based on Human Clinical Trial Results

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $633,656

## Abstract

PROJECT SUMMARY
Glioblastoma (GBM), one of the most fatal of cancers, remains impervious to treatment with the current standard
of care (SOC) therapies. Even immunotherapies like immune checkpoint inhibitors (ICI) have failed for GBM
despite their success with other cancers. One critical reason for this failure is that the GBM tumor
microenvironment (TME) is highly immunosuppressive. To change the GBM microenvironment, we and others
have been utilizing direct intra-tumoral administration of gene therapies that express powerful immune-activators,
both preclinically and clinically. In fact, we have concluded a phase 1 clinical trial of intratumoral administration
of a regulatable interleukin 12 (IL12) immunogene therapy in subjects with recurrent GBM (rGBM)1
(NCT02026271). In this trial, post-injection tumors showed increased inflammatory infiltrates including increased
numbers of CD8+ T cells and elevated levels of tumor IFNγ. However, this also was coupled with increases in
tumor PD-L1 and PD-1 positive cells, characteristic of chronic exhaustion and immune escape. Therefore, the
trial suggested that addition of anti-PD-1 immune checkpoint signaling should be beneficial to IL12 immunogene
therapy efficacy. Based on this, we finished accrual to two multi-institutional clinical trials of intratumoral IL12
immunogene therapy (to increase infiltration of IFNγ producing, CD8+ cytotoxic T cells) coupled with neoadjuvant
immune checkpoint inhibition (ICI) (NCT03636477 and NCT04006119). These trials have shown that the
combination of these two immunotherapies is well tolerated in humans, but unexpectedly there was no
improvement in efficacy by adding ICI. Based on this clinical result, we propose to explore two questions using
preclinical models of GBM: 1- Does the timing of ICI administration with respect to IL12 immunostimulation
change the therapeutic response? 2- Does GBM immune-evasion from IL12 depend on more than single PD-1
signaling? To provide answers to these two questions, we plan to pursue the following aims: Aim 1- Compare
efficacy, tolerability, and immune effects of neo-adjuvant vs. adjuvant anti-PD1 therapy in mouse models
of GBM treated with intratumoral IL12 immunogene therapy, and Aim 2- Test the efficacy, tolerability,
and immune effects of silencing the immunoevasive noncoding RNA, INCR1, when combined with
intratumoral IL12 immunogene therapy.
The impact from these studies will be to significantly inform whether IL12 (or other cytokines) immunogene
therapy can be improved by changing the timing of ICI administration or by targeting a different pathway that
regulates multiple immunoevasive signals, leading us to the next design of clinical trials using cytokine
immunogene therapy.

## Key facts

- **NIH application ID:** 10977809
- **Project number:** 1R01NS134723-01A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** E. Antonio Chiocca
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $633,656
- **Award type:** 1
- **Project period:** 2024-08-22 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10977809

## Citation

> US National Institutes of Health, RePORTER application 10977809, Improving IL12 Immunogene Therapy for Glioblastoma Based on Human Clinical Trial Results (1R01NS134723-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10977809. Licensed CC0.

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