# Network mechanisms and bioengineering of precision immunotherapies for glioblastomas

> **NIH NIH F30** · MAYO CLINIC ROCHESTER · 2021 · $46,236

## Abstract

Project Summary/Abstract
Glioblastoma multiforme (GBM) is the most common and lethal malignancy of the human central nervous
system (CNS). This devastating disease has a median overall survival of 3 months from time of diagnosis in
untreated patients. Despite the significant cost and morbidity with standard of care surgical resection combined
with adjuvant chemotherapy and radiation, life expectancy is only extended by a few months. Oncolytic viruses
(OVs) are a class of immunotherapies with an FDA-approved treatment for solid tumors. These work by
directly lysing tumor cells, which then release tumor antigens with danger signals that elicit antitumor immunity.
Adenovirus is a strong candidate OV immunotherapy for GBM because of its low neurotoxicity when delivered
by intratumoral injection and its amenability to bioengineering. Ad5-Δ24, an adenovirus modified to replicate in
GBM but not in other CNS cells, is perhaps the most promising OV in clinical trials. Major hurdles remain,
however, including innate immunoresistance. This study will overcome these by elucidating complex tumor-OV
interaction mechanisms at the systems level, designing and constructing improved OV candidates that exploit
these mechanisms, and then validating the mechanisms by experimentally testing the OVs. Preliminary studies
for this proposal demonstrate that GBM patient-derived xenograft (PDX) models have distinct transcriptomes in
vivo and can be cultured as neurospheres (Sp-GBMs) under serum-free conditions ex vivo. Ad5-Δ24 OV can
lyse several different Sp-GBMs ex vivo and the level of this oncolytic activity is PDX specific. Additionally,
preliminary in silico models suggest that such OV activity levels are contextually dependent on protein-protein
interaction networks in the target GBM cells. This project will test the central hypothesis that dynamic
transcriptional states of human GBM play key mechanistic roles in Ad5-Δ24 oncolytic efficacy; therefore,
modeling the emergent system behaviors will guide the engineering of precision OV immunotherapies. The first
aim will classify human GBM PDXs using transcriptomes to predict Ad5-Δ24 OV responses and identify
context-specific network features. The resulting classifier and network models will be validated by assessing
their ability to predict the response of Sp-GBM to Ad5-Δ24 OV treatment. The second aim will elucidate Ad5-
Δ24 OV gene dependencies and resistance mechanisms in human GBM PDXs. Predictions from both aims will
both experimentally and computationally validated. Synthetic Ad5-Δ24 OVs with shRNAs that perturb these
gene dependencies and resistance mechanisms will be constructed and tested for efficacy. These precisely
targeted alterations result in the quantifiable, predictable phenotypic effects of modulating human GBM gene
expression and oncolysis ex vivo and in vivo. Such synthetic OVs will be useful as GBM research tools. As a
future direction, the big data generated will be a valuable public resource to fu...

## Key facts

- **NIH application ID:** 10231604
- **Project number:** 1F30CA250122-01A1
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Dileep Daniel Monie
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,236
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10231604

## Citation

> US National Institutes of Health, RePORTER application 10231604, Network mechanisms and bioengineering of precision immunotherapies for glioblastomas (1F30CA250122-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10231604. Licensed CC0.

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