# Chemo-immunotherapy strategy for pediatric high grade glioma

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $429,000

## Abstract

Abstract
Pediatric brain tumors are the leading cause of death in children with cancer in the U.S. Among them, pediatric
high-grade gliomas (pHGGs) are one of the most common and aggressive forms of brain cancer, with a median
survival of 9-15 months.1-3 One of the prominent subgroups of pHGG that arises in cerebral hemispheres
encodes for G34R/V substitutions in the histone H3F3A, along with ATRX and TP53 inactivating mutations.
The current standard of care, consisting of tumor resection followed by radiation and chemotherapy,1-4 only
leads to a modest increase in median survival. One of the reasons for the limited therapeutic outcomes is
tumor recurrence, caused by the spread of pHGG cells that infiltrate the brain.1-4 Treatment effectiveness for
pHGG has also been limited due to the blood-brain barrier (BBB),5 which precludes the efficient delivery of
chemotherapeutic compounds to the tumor mass. Therapeutic strategies involving local delivery of
chemotherapeutic agents to the tumor are emerging as attractive approaches. To explore novel therapeutic
modalities for the G34R/V pHGG subtype, we developed a de novo mouse model harboring the genetic lesions
using the Sleeping Beauty (SB) transposase-mediated system.6-8 Our preliminary data demonstrate that the
H3.3G34R mutation reduces the expression of genes involved with DNA repair, rendering the cells more
susceptible to ionizing radiation in vivo and to DNA damage sensitizers such as Olaparib, a PARP inhibitor. In
this application, we propose to deliver Olaparib into the TME using high-density lipoprotein (HDL)-mimicking
nanodiscs (NDs) that can be specifically internalized into tumor cells via scavenger receptor class B-1 (SR-
B1) and caveolae lipid rafts endocytosis.9 We observed that SR-B1 is expressed in H3.3G34R pHGG
neurospheres (NS) derived from the SB model, as well as in H3.3G34R pHGG patient-derived cells. In this
study, we will develop chemo-immunotherapy delivery vehicles based on sHDL NDs loaded with CpG, a Toll-
like receptor 9 (TLR9) agonist, together with Olaparib, a chemotherapeutic agent, for targeting H3.3G34R
pHGG. We demonstrated that local delivery of sHDL NDs loaded with chemo-immunotherapeutics, in an
intracranial syngeneic mouse glioma model, elicited tumor regression and anti-tumor CD8+ T cell responses
in the brain tumor microenvironment (TME) without overt off-target effects.10 These data indicate that sHDL
NDs are an attractive drug delivery platform for pHGG, which we hypothesize will result in tumor regression
and long-term survival. The proposed delivery system has significant potential for clinical translation.

## Key facts

- **NIH application ID:** 10296214
- **Project number:** 1R21NS123879-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Maria G Castro
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $429,000
- **Award type:** 1
- **Project period:** 2021-07-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296214

## Citation

> US National Institutes of Health, RePORTER application 10296214, Chemo-immunotherapy strategy for pediatric high grade glioma (1R21NS123879-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10296214. Licensed CC0.

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